Spiroindoline modulators of muscarinic receptors

ABSTRACT

The present invention relates to spiroindoline modulators of muscarinic receptors. The present invention also provides compositions comprising such spiroindoline modulators, and methods therewith for treating muscarinic receptor mediated diseases.

CLAIM OF PRIORITY

This Divisional application claims the benefit of U.S. utility application Ser. No. 11/208,386, filed on Aug. 19, 2005, now U.S. Pat. No. 7,879,834, which claims the benefit of U.S. provisional application No. 60/602,731, filed on Aug. 19, 2004, which are hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to modulators of muscarinic receptors. The present invention also provides compositions comprising such modulators, and methods therewith for treating muscarinic receptor mediated diseases.

BACKGROUND OF THE INVENTION

The neurotransmitter acetylcholine binds to two types of cholinergic receptors: the ionotropic family of nicotinic receptors and the metabotropic family of muscarinic receptors. Muscarinic receptors belong to the large superfamily of plasma membrane-bound G protein coupled receptors (GPCRs). To date, five subtypes of muscarinic receptors (M₁-M₅) have been cloned and sequenced from a variety of species, and show a remarkably high degree of homology across species and receptor subtype. These M₁-M₅ muscarinic receptors are predominantly expressed within the parasympathetic nervous system which exerts excitatory and inhibitory control over the central and peripheral tissues and participate in a number of physiologic functions, including heart rate, arousal, cognition, sensory processing, and motor control.

Muscarinic agonists such as muscarine and pilocarpine, and antagonists, such as atropine have been known for over a century, but little progress has been made in the discovery of receptor subtype-selective compounds, thereby making it difficult to assign specific functions to the individual receptors. See, e.g., DeLapp, N. et al., “Therapeutic Opportunities for Muscarinic Receptors in the Central Nervous System,” J. Med. Chem., 43(23), pp. 4333-4353 (2000); Hulme, E. C. et al., “Muscarinic Receptor Subtypes,” Ann. Rev. Pharmacol. Toxicol., 30, pp. 633-673 (1990); Caulfield, M. P. et al., “Muscarinic Receptors—Characterization, Coupling, and Function,” Pharmacol. Ther., 58, pp. 319-379 (1993); Caulfield, M. P. et al., International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors,” Pharmacol. Rev., 50, pp. 279-290 (1998), the disclosures of which are incorporated herein by reference.

The Muscarinic family of receptors is the target of a large number of pharmacological agents used for various diseases, including leading drugs for COPD, asthma, urinary incontinence, glaucoma, Alzheimer's (AchE inhibitors). Despite the large therapeutic value of this family, cholinergic drugs are limited by the lack of selectivity of these agents, with significant activation of the parasympathetic autonomous system and elevated incidence of adverse effects. The molecular cloning of the muscarinic receptors and the identification of the physiological role of specific isoforms using knock-out mice, has recently delineated novel opportunities for selective muscarinic ligands, and has helped to define the selectivity profile that is required for enhanced efficacy and reduced side effects.

There is a need for modulators of muscarinic receptors M₁-M₅. There is also a need for methods for treating muscarinic receptor-mediated diseases.

There is also a need for modulators of muscarinic receptors that are selective as to subtypes M₁-M₅.

SUMMARY OF THE INVENTION

The present invention provides methods of modulating activity of a muscarinic receptor using compounds of formula (I):

and pharmaceutically acceptable salts thereof.

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together form oxo.

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)-, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-, or O.

Z₂ is N.

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—, —S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z) N(Q₂)-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of the formula (III)

in which the monocycloaliphatic group, the monocycloheteroalipahtic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X₁ and ring B, and the monocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄, fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃; bond r is a single or double bond and when ring B is present, bond r is fused with B; ring B, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring; and ring B is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, —N(C(O)—X₂-aliphatic)- in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃;

Each Q₁ is independently halo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂, —S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂, —C(O)-Q₂, —C(O)N(Q₂)₂, —C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂, —N(Q₂)C(O)O-Q₂, —N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3 substituents independently selected from Q₂ or Q₃.

Each Q₂ is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally substituted with 1-3 substituents independently selected from Q₃.

Each Q₃ is halo, oxo, CN, NO₂, CF₃, OCF₃, OH, —S(O)_(z)Q₄, —N(Q₄)₂, —COOQ₄, —C(O)Q₄, —OQ₄, or C₁-C₄ alkyl optionally substituted with 1-3 halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH.

Each Q₄ is aliphatic, cycloaliphatic, aryl, aralkyl, heterocycloaliphatic, heteroaralky, or heteroaryl, each optionally including 1-3 substituents selected from halo, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, or COOH.

Each Q₅ is a heterocyclic ring optionally substituted with 1-3 substituents selected from halo, C₁-C₄ alkyl, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, COOH; and each i is independently 1, 2, or 3; each m and n is independently 1, 2, 3, or 4 provided that m+n is at least 4; each p is 0 or 1; each y is independently 0 or 1; t is 1 to 4; and each z is independently 0, 1, or 2.

Additional aspects of the present invention provide compounds of formula (II), pharmaceutical compositions that are useful modulators of muscarinic receptors, and methods of treating muscarinic receptor mediated diseases using compounds of formulae (I and II).

Advantageously, the compounds of the invention are generally selective for M₁ and M₄ muscarinic receptors. Unexpectedly, the compounds of the invention exhibit increased activity and/or efficacy for M₁ and/or M₄ muscarinic receptors relative to other muscarinic receptors.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following definitions shall apply unless otherwise indicated.

I. Definitions

As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausolito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

The term “muscarinic receptor,” without a prefix specifying the receptor subtype, refers to one or more of the five receptor subtypes M₁-M₅.

The term “modulating” as used herein means increasing or decreasing, e.g. activity, by a measurable amount. Compounds that modulate muscarinic activity by increasing the activity of the muscarinic receptors are called agonists. Compounds that modulate muscarinic activity by decreasing the activity of the muscarinic receptors are called antagonists. An agonist interacts with a muscarinic receptor to increase the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding. An antagonist interacts with a muscarinic receptor and competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor to decrease the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.

The phrase “treating or reducing the severity of a muscarinic receptor mediated disease” refers both to treatments for diseases that are directly caused by muscarinic activities and alleviation of symptoms of diseases not directly caused by muscarinic activities. Examples of diseases whose symptoms may be affected by muscarinic activity include, but are not limited to, CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes, Huntington's Chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, Parkinson's disease, peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjögren's Syndrome, bradhycardia, gastric acid secretion, asthma, GI disturbances and wound healing.

As used herein the term “aliphatic’ encompasses the terms alkyl, alkenyl, alkynyl.

As used herein, an “alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can be optionally substituted with one or more substituents such as halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxyl. Without limitation, some examples of substituted alkyls include alkylcarbonylalkyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carbonylalkyl, carboxyalkyl, hydroxyalkyl, oxoalkyl, aralkyl, alkoxyaralkyl, (alkylsulfonylamino)alkyl, (sulfonylamino)alkyl, carbonylaminoalkyl, aminocarbonylalkyl, cycloaliphaticalkyl, cyanoalkyl, aminoalkyl, oxoalkyl, alkoxycarbonylalkyl, (alkoxycarbonylheterocycloalkyl)alkyl, (cycloalkyl)alklyl, (cycloalkenyl)alkyl, (heterocycloalkyl)alkyl, or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group may be optionally substituted with one or more substituents such as halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one triple bond. Like an alkyl group, an alkynyl group can be straight or branched. An alkynyl group may be optionally substituted with one or more substituents such as halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, or hydroxyl.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each of R^(X) and R^(Y) is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or carbonyl each of which are defined herein and are optionally substituted. Examples of amino groups include alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, (azacycloalkylcarbonyl)amino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, cycloalkylcarbonylamino. When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by —NR^(X)—. R^(X) has the same meaning as defined above. A nonexhaustive list of possible R^(X) and R^(Y) includes sulfonylamino, alkylamino, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or heteroaralkylcarbonyl.

As used herein, a “carbonyl” group, when used alone or as part of another structure refers to —(CO)R^(X), where R^(X) is defined above. When the term “carbonyl” is not the terminal group (e.g., arylaminoalkylcarbonyl) it is represented by —C(O)R^(X). Without limitation, carbonyl groups can include optionally substituted aminocarbonyl, alkoxyalkoxycarbonyl, alkylaminocarbonyl, arylcarbonyl (e.g., haloarylcarbonyl), heterocycloalkylcarbonyl, heterocycloalkenylcarbonyl, arylaminocarbonyl (e.g., haloarylaminocarbonyl), cyanoalkylarylcarbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkoxyarylcarbonyl (e.g., haloalkoxyarylcarbonyl), (alkylheterocyclo)alkenylcarbonyl, heteroarylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl (e.g., haloalkoxycarbonyl), alkylarylcarbonyl, cycloalkylcarbonyl, alkylheteroarylcarbonyl, arylsulfonylcarbonyl, aminocarbonyl, sulfonylcarbonyl, alkylcarbonyl, alkylsulfonylcarbonyl, alkylcarbonyl, arylaminocarbonyl, or the like. A nonexhaustive list of possible R^(X) and R^(Y) includes sulfonylaminocarbonyl, alkylcarbonyl, carbonylamino, carboxy, oxo, hydroxyl, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylalkylcarbonyl, heteroarylcarbonyl, or heteroaralkylcarbonyl.

As used herein, an “aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, anthracenyl, or tetrahydroanthracenyl); or a benzofused group having 3 rings. For example, a benzofused group includes phenyl fused with two or more C₄₋₈ carbocyclic moieties. An aryl is optionally substituted with one or more substituents including aliphatic (e.g., alkyl, alkenyl, or alkynyl); cycloalkyl; (cycloalkyl)alkyl; heterocycloalkyl; (heterocycloalkyl)alkyl; aryl; heteroaryl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl; amino; aminoalkyl; nitro; carboxy; carbonyl (e.g., alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, (alkylamino)alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl; or sulfonylcarbonyl); aryalkylcarbonyloxy; sulfonyl (e.g., alkylsulfonyl or aminosulfonyl); sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); cyano; halo; hydroxyl; acyl; mercapto; sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. Alternatively, an aryl may be unsubstituted.

Examples of substituted aryls include haloaryl, alkoxycarbonylaryl, alkylaminoalkylaminocarbonylaryl, p,m-dihaloaryl, p-amino-p-alkoxycarbonylaryl, m-amino-m-cyanoaryl, aminoaryl, alkylcarbonylaminoaryl, cyanoalkylaryl, alkoxyaryl, aminosulfonylaryl, alkylsulfonylaryl, aminoaryl, p-halo-m-aminoaryl, cyanoaryl, hydroxyalkylaryl, alkoxyalkylaryl, hydroxyaryl, carboxyalkylaryl, dialkylaminoalkylaryl, m-heterocycloaliphatic-o-alkylaryl, heteroarylaminocarbonylaryl, nitroalkylaryl, alkylsulfonylaminoalkylaryl, heterocycloaliphaticcarbonylaryl, alkylsulfonylalkylaryl, cyanoalkylaryl, heterocycloaliphaticcarbonylaryl, alkylcarbonylaminoaryl, hydroxyalkylaryl, alkylcarbonylaryl, aminocarbonylaryl, alkylsulfonylaminoaryl, dialkylaminoaryl, alkylaryl, and trihaloalkylaryl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., a C₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” are defined herein. An example of an aralkyl group is benzyl. A “heteroaralkyl” group refers to an alkyl group that is substituted with a heteroaryl. Both “alkyl” and “heteroaryl” are defined herein.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring structures include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics (e.g., bicycloheteroalkyl or bicycloheteroalkenyl), bicyclic aryls, and bicyclic heteroaryls.

The term “cycloaliphatic” means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon ring that has a single point of attachment to the rest of the molecule. Cycloaliphatic rings are 3-8 membered monocyclic rings (e.g., 3-6 membered rings). Cycloaliphatic rings also include 8-12 membered bicyclic hydrocarbon rings, (e.g., 10 membered bicyclic hydrocarbon rings). A cycloaliphatic group encompasses a “cycloalkyl” group and a “cycloalkenyl” group.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclic mono-, bi-, or tri-, or multicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Without limitation, examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like. Without limitation, examples of bicyclic cycloalkyl groups include octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, bicycle[2.2.1]heptanyl, bicycle[3.1.1]heptanyl, or the like. Without limitation, multicyclic groups include adamantyl, cubyl, norbornyl, or the like. Cycloalkyl rings can be optionally substituted at any chemically viable ring position.

A “cycloalkenyl” group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl. Cycloalkenyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.

A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxyl, acyl, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, or the like.

Without limitation, examples of substituted cycloaliphatics include alkylcycloalkyl (e.g., propylcyclohexyl), alkylbicyclo[3.1.1]heptyl, alkylcycloalkenyl, or the like.

As used herein, the term “heterocycloaliphatic” and “heterocyclic” encompasses a heterocycloalkyl group and a heterocycloalkenyl group.

As used herein, a “heterocycloalkyl” group refers to a 3-10 membered mono or bicyclic (fused or bridged) (e.g., 5 to 10 membered mono or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of a heterocycloalkyl group include optionally substituted piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octanyl, 2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl, tropane. A monocyclic heterocycloalkyl group may be fused with a phenyl moiety such as tetrahydroisoquinoline. Heterocycloalkyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.

A “heterocycloalkenyl” group, as used herein, refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Examples of heterocycloalkenyls include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, or 2-pyrazolyl. Monocyclic heteroaliphatics are numbered according to standard chemical nomenclature. For instance:

A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl (such as a benzimidazolidinyl), (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxyl, acyl, mercapto, sulfonyl (such as alkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

Without limitation, examples of substituted heterocycloaliphatics include alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonyltropane), alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonylpiperidyl), or the like.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic. A heteroaryl group includes a benzofused ring system having 2 to 3 rings. For example, a benzofused group includes benzo fused with one or two C₄₋₈ heterocyclic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:

Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. For instance:

A heteroaryl is optionally substituted with one or more substituents such as aliphatic including alkyls (e.g., alkoxyalkyl, carboxyalkyl, hydroxyalkyl, oxoalkyl, aralkyl, (alkylsulfonylamino)alkyl, (sulfonylamino)alkyl, cyanoalkyl, aminoalkyl, oxoalkyl, alkoxycarbonylalkyl, (cycloalkyl)alkyl heterocycloalkyl, (heterocycloalkyl)alkyl aralkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl; cycloaliphatic including cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); heterocycloaliphatic including heterocylcoalkyli (e.g., thiomorpholyl, piperazinyl, 1,3,5-trithianyl, morpholinyl, pyrrolyl, 1,3-dioxolanyl, pyrazolidyl, or piperidinyl); aryl, heteroaryl (e.g., quinolyl, indolyl, 3H-indolyl, isoindolyl, benzo[b]-4H-pyranyl, cinnolyl, quinoxylyl, benzimidazyl, benzo-1,2,5-thiadiazolyl, benzo-1,2,5-oxadiazolyl, or benzthiophenyl); alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heteroaroyl; amino (e.g., carbonylamino, alkylcarbonylamino, alkylsulfonylamino, arylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkyl)alkylcarbonylamino, sulfanylamino, and (heterocycloalkyl)alkylcarbonylamino); nitro; carboxy; carbonyl (e.g., alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, arylaminocarbonyl, thiazoleaminocarbonyl, thiomorpholinecarbonyl, aminoalkylaminocarbonyl); alkylcarbonyloxy; cyano; halo; hydroxyl; acyl; mercapto; sulfonyl (e.g., aminosulfonyl, alkylsulfonyl, morpholinesulfonyl, or arylsulfonyl); sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo; or carbamoyl.

Examples of substituted heteroaryls include haloheteroaryl, alkoxycarbonylheteroaryl, alkylaminoalkylaminocarbonylheteroaryl, dihaloheteroaryl, cyanoheteroaryl, aminoheteroaryl, alkylcarbonylaminoheteroaryl, cyanoalkylheteroaryl, alkoxyheteroaryl, aminosulfonylheteroaryl, alkylsulfonylheteroaryl, aminoheteroaryl, aminoheteroaryl, hydroxyalkylheteroaryl, alkoxyalkylheteroaryl, hydroxyheteroaryl, carboxyalkylheteroaryl, dialkylaminoalkylheteroaryl, heterocycloaliphaticheteroaryl, heteroarylaminocarbonylheteroaryl, nitroalkylheteroaryl, alkylsulfonylaminoalkylheteroaryl, heterocycloaliphaticcarbonylheteroaryl, alkylsulfonylalkylheteroaryl, cyanoalkylheteroaryl, heterocycloaliphaticcarbonylheteroaryl, alkylcarbonylaminoheteroaryl, hydroxyalkylheteroaryl, alkylcarbonylheteroaryl, aminocarbonylheteroaryl, alkylsulfonylaminoheteroaryl, dialkylaminoheteroaryl, alkylheteroaryl, and trihaloalkylheteroaryl.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g., a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.

As used herein, “cyclic moiety” includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which has been defined previously.

As used herein, an “acyl” group refers to a formyl group or alkyl-C(═O)— (also referred to as “alkylcarbonyl”) where “alkyl” has been defined previously. Acetyl and pivaloyl are examples of acyl groups.

As used herein, a “carbamoyl” group refers to a group having the structure —O—CO—NR^(x)R^(y) or —NR^(x)—CO—O—R^(z) wherein R^(x) and R^(y) have been defined above and R^(z) can be alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.

As used herein, a “carboxy” and a “sulfo” group refer to —COOH or —COOR^(X) and —SO₃H or —SO₃R^(X), respectively.

As used herein, an “alkoxy” group refers to an alkyl-O— group where “alkyl” has been defined previously. Moreover an alkoxy group includes structures comprising two alkoxy groups on the same atom or adjacent atoms that form a ring together with the atom(s) to which they are bound.

As used herein, a “sulfoxy” group refers to —O—SO—R^(X) or —SO—O—R^(X), where R^(X) has been defined above.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X), wherein R^(X) has been defined above. Examples of sulfonyls include optionally substituted alkylsulfonyl, arylsulfonyl (e.g., haloarylsulfonyl), heteroarylsulfonyl (e.g., alkylheteroarylsulfonyl), or the like.

As used herein a “sulfinyl” group refers to —S(O)—R_(X), wherein R^(X) has been defined above. Examples of sulfinyls include alkylsulfinyl.

As used herein a “sulfanyl” group refers to —S—R_(X), wherein R^(X) has been defined above. Examples of sulfanyls include alkylsulfanyl.

As used herein, a “halogen” or “halo” group refers to fluorine, chlorine, bromine or iodine.

As used herein, a “haloaliphatic” group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group —CF₃.

As used herein, a “sulfamoyl” group refers to the structure —S(O)₂—NR^(x)R^(y) or —NR^(x)—S(O)₂—R^(z) wherein R^(x), R^(y), and R^(z) have been defined above.

As used herein, a “sulfamide” group refers to the structure —NR^(X)—S(O)₂—NR^(Y)R^(Z) wherein R^(X), R^(Y), and R^(Z) have been defined above.

As used herein, a “carbonylamino” group used alone or in connection with another group refers to an amido group such as Rx-C(O)—NR^(X)—. For instance an alkylcarbonylamino includes alkyl-C(O)—NR^(X)—, wherein R^(x) has been defined above.

As used herein, a “aminocarbonyl” group used alone or in connection with another group refers to an amido group such as N(Rx)₂-C(O)—.

As used herein, an “alkoxycarbonyl” used alone or in connection with another group refers to a carbonyl group such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, an “aminocarbonyl” refers to an amido group such as —NR^(X)—C(O)—, wherein R^(x) has been defined above.

As used herein, an “aminosulfonyl” refers to the structure —N(R^(X))₂—S(O)₂—, wherein R^(x) has been defined above.

As used herein, an “oxo” refers to ═O.

As used herein, an “aminoalkyl” refers to the structure N(R^(X))₂-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (CN)-alkyl-.

As used herein, an “alkylsulfonyl” group refers to the structure alkyl-S(O)₂—.

As used herein, a “sulfonylamino” group refers to the structure Rx—S(O)₂—N(R^(X))₂—, wherein R^(x) has been defined above.

As used herein, a “urea” group refers to the structure —NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure —NR^(X)—CS—NR^(Y)R^(Z). R^(X), R^(Y), and R^(Z) have been defined above.

In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, may be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). As used herein, “patient” refers to a mammal, including a human.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

II. Compounds

The present invention provides methods of modulating muscarinic receptor activity using compounds of formulae (I and II), described above, that are useful in modulating activity of a muscarinic receptor.

Methods of modulating muscarinic receptors according to one aspect of the present invention involve compounds of formula (I):

or pharmaceutically acceptable salts thereof.

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together form oxo.

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)-, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-, or O.

Z₂ is N.

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—, —S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z) N(Q₂)-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of the formula (III)

in which the monocycloaliphatic group, the monocycloheteroalipahtic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X₁ and ring B, and the monocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄, fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃; bond r is a single or double bond and when ring B is present, bond r is fused with B; ring B, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring; and ring B is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)—, —N(C(O)—X₂-aliphatic)- in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.

Each Q₁ is independently halo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂, —S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂, —C(O)-Q₂, —C(O)N(Q₂)₂, —C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂, —N(Q₂)C(O)O-Q₂, —N(Q₂)S(O)_(z)Q₂ or aliphatic optionally including 1-3 substituents independently selected from Q₂ or Q₃.

Each Q₂ is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q₃.

Each Q₃ is halo, oxo, CN, NO₂, CF₃, OCF₃, OH, —S(O)_(z)Q₄, —N(Q₄)₂, —COOQ₄, —C(O)Q₄, —OQ₄, or C₁-C₄ alkyl optionally substituted with 1-3 of halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NHz, or —COOH.

Each Q₄ is aliphatic, cycloaliphatic, aryl, aralkyl, heterocyclic, heteroaralyl, or heteroaryl ring, each optionally substituted with 1-3 substituents selected from halo, oxo, CN, NO₂, CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, —COOH.

Each Q₅ is a heterocyclic ring optionally substituted with 1-3 substituents selected from halo, C₁-C₄ alkyl, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, COOH; and each i is independently 1, 2, or 3.

Each m and n is independently 1, 2, 3, or 4 provided that m+n is at least 4.

Each p is 0 or 1.

Each y is independently 0 or 1; each t is 1 to 4; and each z is independently 0, 1, or 2.

Another aspect of the invention provides compounds of formula (II) including:

or pharmaceutically acceptable salts thereof.

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together form oxo.

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)—, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-, or O.

Z₂ is N.

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—, —S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z) N(Q₂)-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of formula (III)

in which the monocycloaliphatic group, the monocycloheteroaliphatic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X₁ and ring B, and the monocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄, fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃; bond r is a single or double bond and when ring B is present, bond r is fused with B; ring B, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring, and is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, —N(C(O)—X₂-aliphatic)- in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.

Each Q₁ is independently halo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂, —S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂, —C(O)-Q₂, —C(O)N(Q₂)₂, —C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂, —N(Q₂)C(O)O-Q₂, —N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3 substituents independently selected from Q₂ or Q₃.

Each Q₂ is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally substituted with 1-3 substituents independently selected from Q₃.

Each Q₃ is halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —S(O)_(z)Q₄, —N(Q₄)₂, —COOQ₄, —C(O)Q₄, —OQ₄, or C₁-C₄ alkyl optionally substituted with 1-3 halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH.

Each Q₄ is aliphatic, cycloaliphatic, aryl, aralkyl, heterocycloaliphatic, heteroaralky, or heteroaryl, each optionally including 1-3 substituents selected from halo, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, or COOH.

Each Q₅ is a heterocyclic ring optionally substituted with 1-3 substituents selected from halo, oxo, C₁-C₄alkyl, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, and —COOH.

Each i is independently 1, 2, or 3.

Each p is 0 or 1.

Each y is independently 0 or 1.

Each z is independently 0, 1, or 2.

III. Specific Embodiments a. Substituent G

G is a monocycloaliphatic group, a monocycloheteroaliphatic group, adamantyl, or a bicyclic or a tricyclic group of formula (III)

in which the monocycloaliphatic group, the monocycloheteroaliphatic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X₁ and ring B, and the monocycloaliphatic, the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄, fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃; bond r is a single or double bond and when ring B is present, bond r is fused with B; ring B, when present, is a 5-6 membered cycloaliphatic or heterocyclic ring, and is optionally substituted with 1-3 of oxo, Q₁, or Q₂.

In certain embodiments, G is an optionally substituted monocycloaliphatic group.

In several embodiments, G is an optionally substituted cycloaliphatic. In examples of this embodiment, G is an optionally substituted monocycloaliphatic. Specific examples of G include, but are not limited to, 5 to 8 membered monocycloalkyls or a 5 to 8 membered monocycloalkenyls. In other examples, G can be an optionally substituted cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, or cyclooctyl.

In several embodiments, G is optionally substituted with Q₂, or —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃. In examples of these embodiments, G can be substituted with carbonyl, sulfonyl, alkoxy, combinations thereof, or the like.

In several embodiments, G is optionally substituted with 1 to 3 of carbonyl, sulfonyl, or combinations thereof. Examples of G include, but are not limited to, alkoxycarbonyl, aliphaticcarbonyl (e.g., alkylcarbonyl, alkenylcarbonyl, or alkynylcarbonyl), aliphatic, alkoxyalkoxycarbonyl, cycloalkoxycarbonyl, heterocycloalkoxycarbonyl, aminoaliphatic, aliphaticamino, arylcarbonyl, or heteroarylcarbonyl, each of which is optionally substituted.

In several embodiments, G is substituted with alkyl, aryl, haloalkyl, alkoxycarbonyl, or alkoxyamino.

In several embodiments, G is selected from

In several embodiments, G is an optionally substituted monoheterocycloaliphatic group. Examples of G include, but are not limited to, optionally substituted 5 to 7 membered monoheterocycloaliphatic groups.

In several embodiments, G includes at least 1 nitrogen atom. G can be substituted with 1 to 3 substituents independently selected from Q₂, and —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.

In several embodiments, G is optionally substituted with 1 to 2 substituents independently selected from alkoxycarbonyl, alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl, heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl.

In other embodiments, G is one selected from

In several embodiments, G includes at least one O atom. In several examples, G is optionally substituted with 1 to 3 substituents independently selected from independently selected from alkoxycarbonyl, alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl, heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl. In other examples, G is unsubstituted.

In several embodiments, G is one selected from

In other embodiments, G is an optionally substituted bicyclic group of formula (III). In one group of examples, ring B is absent from the bicyclic group of formula (III).

In several embodiments, X₁ is —(CH)_(2i)—.

In several alternative embodiments, the bicyclic group of formula (III) includes 7 to 9 ring atoms. In specific examples, G is an optionally substituted bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptanyl. In yet another group of the examples, G can be substituted with 1 to 3 substituents independently selected from Q₂, and —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.

In several embodiments, G is one selected from

In other embodiments, G is optionally substituted adamantly.

In several embodiments, X₁ is —N(Q₂)- or —N(C(O)—X₂-aliphatic), where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃. In one group of examples, G is an optionally substituted tropane.

In other examples, G is substituted with Q₂, and —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.

In several embodiments, G is substituted with alkoxycarbonyl, alkoxyalkoxycarbonyl, heterocycloalkoxycarbonyl, cycloalkoxycarbonyl, alkoxyaryloxycarbonyl, alkylaminocarbonyl, haloalkoxycarbonyl, alkynyloxycarbonyl, or heterocycloalkylalkoxycarbonyl.

In several embodiments, G is one selected from

b. Substituent Z₁

Z₁ is —C(Q₁)₂-, —C(H)(Q₁)-, —C(H)(Q₅)-, —C(O)—, —CH₂—, —N(Q₁)-, —N(Q₂)-, or O.

In several embodiments, Z₁ is optionally substituted carbon or nitrogen atom. In one group of examples, Z₁ is substituted with amino, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, aminocarbonyl, alkylcarbonylalkyl, alkoxyalkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, alkoxycarbonyl, haloarylcarbonyl, haloarylsulfonyl, alkylheteroarylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, haloarylaminocarbonyl, alkylheteroarylsulfonyl, cyanoalkylarylcarbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkoxyarylcarbonyl, haloalkoxycarbonyl, alkylarylcarbonyl, haloalkoxyarylcarbonyl, or arylaminocarbonyl.

In several embodiments, Z₁ is one selected from —CH₂—, —C(O)—, —NH—, —O—,

c. Substituents R₁, R₂, and R₃

Each of R₁, R₂, R₃ is independently Q₁ or Q₂, or R₂ and R₃ together form oxo.

In several embodiments, R₁ is hydrogen, halo, or optionally substituted alkyl, heteroaryl, alkoxy, alkenyl, cycloalkyl, cyanoalkylaryl, alkylaryl, alkylsulfonylaryl, alkylcarbonylaryl, aryl, aminocarbonylaryl, alkylcarbonylaminoaryl, cycloalkenyl, or alkoxyaryl. R₁ groups can be optionally substituted with 1 to 3 substituents selected from amino, carbonyl, alkoxycarbonyl, aminocarbonyl, aryl, aliphatic, alkoxy, and sulfonyl.

In other embodiments, R₁ is one selected from hydrogen, halo, methyl, —OCH₃,

In several embodiments, R₂ and R₃ are independently hydrogen, alkyl, arylalkyl, or R₂ and R₃ together form an oxo or amino.

In still other embodiments, R₂ and R₃ are independently hydrogen, alkyl, or R₂ and R₃ together form an oxo.

d. L Groups

L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—, —S(O)_(z)—(C₁-C₄)alkyl-, —C(O)N(Q₂)-, or —S(O)_(z)N(Q₂)-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂. In some embodiments, L is a bond or an aliphatic group in which the aliphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂. In other embodiments, L is a bond. In still further embodiments, L is an aliphatic group optionally substituted with 1-3 of oxo, Q₁, or Q₂. L is CH₂.

e. Combinations of Embodiments

Other embodiments include any combination of the aforementioned substituents G, Z₁, L, R₁, R₂, and R₃.

f. Excluded Compounds

In several embodiments, when Z₁ is —CH₂— or —N(CH₃)—, L is a bond, and G is an optionally substituted monocycloaliphatic, an optionally substituted monocycloheteroalipahtic group, or a norbornanyl group, then the R₁ substituent on the indane or indole is other than H.

In several embodiments, when L is —C(O)—CH₂— and Z₁ is —N(Q₁)-, and Q₁ on Z₁ is —S(O)₂-optionally substituted phenyl, then the R₁ substituent on the indole is other than H.

In several embodiments, when L is —S(O)₂—(C₁-C₄)alkyl-, Z₁ is —CH₂—, then the R₁ substituent on the indane or tetrahydronaphthyl is other than H.

In several embodiments, when L is —S(O)₂—(C₁-C₄)alkyl-, R₂ and R₃ form ═O, Z₁ is —N(Q₁)-, and Q₁ is aliphatic or —S(O)₂-aliphatic, then the R₁ substituent on the indole is other than H.

In several embodiments, when L is aliphatic, and R₂ and R₃ form ═O, and Z₁ is —N(Q₁)-, Q₁ is aliphatic, G is a substituted monocycloheteroaliphatic group, then the R₁ substituent on the indole is other than H.

In certain embodiments, L is not —S(O)₂—(C₁-C₄)alkyl-.

g. Specific Embodiments

Specific compounds of formulae (I or II) are shown below. Compounds 1-120 and 122-430 share the core structure of formula II.

TABLE 1 Specific Compounds  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

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Index: 1 VRT-820652 None

Index: 2 VRT-818269 ++

Index: 3 VRT-819957 +

Index: 4 VRT-820646 None

Index: 5 VRT-820649 None

Index: 6 VRT-820650 None

Index: 7 VRT-819611 +

Index: 8 VRT-819617 ++

Index: 9 VRT-819612 +

Index: 10 VRT-819608 ++

Index: 11 VRT-819435 ++

Index: 12 VRT-819610 ++

Index: 13 VRT-819616 ++

Index: 14 VRT-819606 ++

Index: 15 VRT-819614 ++

Index: 16 VRT-819615 ++

Index: 17 VRT-819613 ++

Index: 18 VRT-819907 ++

Index: 19 VRT-819904 ++

Index: 20 VRT-819909 ++

Index: 21 VRT-819905 ++

Index: 22 VRT-819603 ++

Index: 23 VRT-819604 ++

Index: 24 VRT-819607 ++

IV. Synthetic Schemes

The compounds of formulae (I and II) may be readily synthesized from commercially available starting materials using methods known in the art. Exemplary synthetic routes to produce compounds of formulae (I and II), are provided below in Preparations A-F and Schemes 1-10. For simplicity of illustration, schemes 1-10 depict only a single R₁ substituent on the fused phenyl ring of formulae I and II, the compounds of this invention may include 1 to 4 R₁ substituents on the fused phenyl ring.

Scheme 1 below depicts general conditions for the synthesis of compounds of formula (I).

The reaction of amine (A) with an appropriate aldehyde or ketone under reductive amination conditions (step a), typically using NaBH(OAc)₃ in DCE/AcOH/TEA at room temperature, may be used to provide the desired compounds of formula I. For less reactive ketones, more forcing conditions may be used. For example, the treatment of the amine (A) and the ketone in a neat solution of Ti(OiPr)₄, followed by treatment with NaBH₄ in MeOH, may be used to provide the desired compounds of formula I. See Abdel-Magid, A. F. et al., “Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures,” J. Org. Chem., 61, pp. 3849-3862 (1996) and the references sited therein.

Alternatively, the of spiroamine of type A may be alkylated with an alkyl halide in the presence of an appropriate base to provide the desired compounds of formula I. Typically, the amine (A) is reacted with an alkyl iodide, bromide, or chloride in the presence of an appropriate base to yield compounds of formula I. Bases may be organic such as triethylamine, or inorganic such as Na₂CO₃ or Cs₂CO₃. Typical reaction solvents include but are not limited to DMF, acetone, and acetonitrile.

Scheme 2 illustrates alternative conditions for the synthesis of compounds of formula I in which Z₁ is —C(H)₂— and R₂ and R₃ are hydrogen (Synthetic route A), or in which Z₁ is —C(O)— (Synthetic route B).

Compounds of type i in Scheme 2 may be prepared using procedures as described in Evans, B. E, et al., J. Med. Chem. 1992, 35, 3919 and M. S. Chambers J. Med. Chem. 1992, 35, 2033. Intermediate compounds may be produced from compound of type i using the following conditions: (a) KMnO₄ oxidation, TBAB, aqueous KOH (b) NaH, X—R₂ and/or X—R₃, THF (c) Ammonium formate, MeOH, Pd/C, room temperature or heat; or Pd/C, MeOH, H₂; or if PG=Boc, then TFA, CH₂Cl₂, −10° C.; (d) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃, acetonitrile, heat.

Scheme 3 illustrates alternative conditions for the synthesis of compounds of formula I in which Z₁ is —O— and R₂ and R₃ are hydrogen.

Amines of type iv in Scheme 3 were prepared using procedures analogous to those found in the following references: WO 96/11934 “Tricyclic spiro compounds process for their preparation” and U.S. Pat. No. 6,013,652A “Spiro-substituted azacyclics as neurokinin antagonists”. Conditions: (a) Ph₃P/DEAD (b) Bu₃SnH, AIBN (c) Ammonium formate, MeOH, Pd/C, room temperature or heat; or Pd/C, MeOH, H₂; or if PG=Boc, then TFA, CH₂Cl₂, −10° C.; (d) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃, acetonitrile, heat.

Scheme 4 illustrates alternative conditions for the synthesis of compounds of formula I in which Z₁ is —N(Q1)- and R₂ and R₃ are hydrogen.

Amines of type i in Scheme 4 may be prepared from methods known in the art and by using procedures analogous to those found in the following references: WO 03/106457 “Spiroindolinepiperidine Derivatives”; Maligres, P. E., et al., Tetrahedron, 1997, 53, 10983-10992; Cheng, Y. and Chapman, K. T., Tet. Lett. 1997, 38, 1497-1500; U.S. Pat. No. 6,013,652A “Spiro-substituted azacyclics as neurokinin antagonists”. Conditions: (a) amine protection orthoganol to PG₁; (b) amine deprotection of PG₁ (e.g. PG₁=Boc: TFA, CH₂Cl₂, −10° C.); (c) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃, acetonitrile, heat; (d) Q₂X (Q₂ may be, for example, H and aliphatic, X is halogen), K₂CO₃, DMF/THF, RT to 60° C.; or electrophile (e.g. RSO₂Cl, RCOCl, ROC(═O)Cl, where R is H or Q₂, TEA, CH₃CN.

Reaction of i with intermediate under palladium cross coupling conditions (step a) Pd(dppf)Cl2 or (Ph₃P)₄Pd, 2M K₂CO₃, and acetonitrile under microwave irradiation at 150° C. for 10-20 minutes yields compound II. Unsaturated compounds of type ii may be further elaborated (e.g. reduction; oxidation) to provide additional compounds of formula (I).

Scheme 6 illustrates alternative conditions for the synthesis of compounds of formula I in which Z₁ is —N(Q₁)- or —N(Q₂)-, R₂ and R₃ together form oxo, and p=1.

Compound i may be produced by methods disclosed above and by those known in the art. Intermediate compounds may be produced from compounds of type i using the following conditions: (a) NH₂OH.HCl; (b) 2,4,6-trichloro-1,3,5-triazine; (c) PG=Bn or Cbz; Ammonium formate, MeOH, Pd/C, room temperature; or Pd/C, MeOH, H₂; (d) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃, acetonitrile, heat; (e) optional alkylation, NaH, THF, appropriate alkyl halide.

Scheme 7 illustrates alternative conditions for the synthesis of compounds of formula I in which Z₁ is —CH(Q₁)- and R₂ and R₃ are hydrogen.

Compound i may be produced by methods disclosed above and by those known in the art. Compounds II through ix may be produced from compound i using the following conditions: (a) ZnCl₂ or other Lewis acid, (R)- or (S)-1-phenylethanamine, PhCH₃ reflux, Dean-Stark; (b) NaBH₄, MeOH, −30° C.; (c) Q₂′X (Q₂′ may be, for example, H and aliphatic, X is halogen), K₂CO₃, DMF/THF, RT to 60° C. (d) Ammonium formate, MeOH, Pd/C, room temperature; or Pd/C, MeOH, H₂; (e) electrophile (e.g. RSO₂Cl, RCOCl, ROC(═O)Cl, where R is H or alkyl, and Q₂″ is RSO₂—, ROC(O)—, ROC(O)—, TEA, CH₃CN; (f) PG=Boc: TFA, CH₂Cl₂, −10° C.; (g) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃, acetonitrile, heat.

Scheme 8 illustrates alternative conditions as example for the synthesis of compounds of formula I in which Ring G contains or is substituted with a protected functionality which may be either be retained, deprotected and retained, or deprotected and further elaborated to produce additional compounds of formula I.

Compound i may be produced by methods disclosed above and by those known in the art. Compounds II through iv may be produced from compound i using the following conditions: (a) e.g. PG=ketal: AcOH/H₂O, heat; PG=Boc: TFA, CH₂Cl₂; (b) e.g. if ring G is substituted by oxo, the compound of formula I may be further elaborated to the oxime: NH₂—O-Q₂, pyridine; (c) e.g. if ring G contains or is substituted by —NH— or —N(Q₂)-, it may be elaborated with an appropriate electrophile to produce iv.

Scheme 9 illustrates alternative conditions for the synthesis of compounds of formula I in which Z₁ is —N(Q₁)- or —N(Q₂)-, and R₂ and R₃ are oxo, and p=0.

Compounds of type i may be purchased commercially or produced by methods known in the art. Conditions: (a) NaH/HMDS/THF; (b) e.g. PG=Bn: Pd(OH)₂; (c) NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH; or the appropriate alkyl halide, Cs₂CO₃, acetonitrile, heat.

Scheme 10 outlines the general preparation of the appropriate aldehydes from the corresponding ketone.

Ketone electrophiles of type i may be purchased commercially or produced by methods disclosed above and by those known in the art. Aldehydes of type ii may be purchased commercially or produced from compounds of type i using the following conditions: (a) Ph₃P⁺CH₂OMeCl⁻, NaN(SiMe₃)₂; (b) aqueous HCl, CH₃CN. The following conditions may be used for the synthesis of compounds of formula I using ketones of type i and aldehydes of type ii: (c) Spiro-amine of type A (see Scheme 1), NaBH(OAc)₃, DCE, AcOH, TEA, appropriate ketone or aldehyde; or i. neat Ti(OiPr)₄, appropriate ketone; ii. NaBH₄, MeOH.

V. Formulations, Administrations, and Uses

The present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention. A “pharmaceutically acceptable prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof. Preferred prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment relative to the parent species.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the modulator can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Depending upon the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

According to a preferred embodiment, the compounds of formulae (I and II) are selective modulators of M₁, M₂ and M₄. More preferably, the compounds of formulae (I and II) are selective modulators of M₁ and/or M₄. Yet more preferably, certain compounds of formulae (I and II) are selective modulators of M₁. Or, preferably, certain compounds of formulae (I and II) are selective modulators of M₄.

Applicants believe that the ability of the compounds of the present invention to modulate the activity of muscarinic receptors is derived from the affinity of these compounds to the muscarinic receptors. Such affinity, applicants believe, activates a muscarinic receptor (i.e., an agonist) or inhibits the activity of a muscarinic receptor.

The term “selective” as used herein means a measurably greater ability to modulate one muscarinic receptor subtype when compared to the other muscarinic receptor subtypes. E.g., the term “selective M₄ agonist” means a compound that has a measurably greater ability to act as an M₄ agonist when compared to that compound's agonist activity with the other muscarinic receptor subtype(s).

According to an alternative embodiment, the present invention provides a method of treating a muscarinic receptor mediated disease in a mammal, such as a human, including the step of administering to said mammal a composition comprising a compound of formulae I and II, or an embodiment thereof as set forth herein.

According to another embodiment, the present invention provides a method of treating a disease mediated by a muscarinic receptor including the step of administering to said mammal a composition comprising a compound of formulae (I and II), or other embodiments thereof as set forth above. Preferably, said disease is mediated by M₁, or said disease is mediated by M₄.

According to yet another embodiment, the present invention provides a method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes, Huntington's Chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, sudden infant death syndrome, Parkinson's disease, peripheral disorders such as reduction of intra ocular pressure in Glaucoma and treatment of dry eyes and dry mouth including Sjögren's Syndrome, wherein said method comprises the step of contacting said patient with a compound according to the present invention.

According to an alternative embodiment, the present invention provides a method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from pain, psychosis (including schizophrenia, hallucinations, and delusions), Alzheimer's disease, Parkinson's disease, glaucoma, bradhycardia, gastric acid secretion, asthma, or GI disturbances.

According to a preferred embodiment, the present invention is useful for treating or reducing the severity of psychosis, Alzheimer's disease, pain, or Parkinson's disease.

All references cited within this document are incorporated herein by reference.

VII. Preparations and Examples

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

Preparation A: Synthesis of N-(ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octane-3-carbaldehyde

Sodium bis(trimethylsilyl)amide (6 mmol, 6 mL of 1 M solution in THF) was added to a suspension of 2.06 g (6.0 mmol) of methoxymethyltriphenylphosphonium chloride in 6 mL of THF at 0° C. under argon. After stirring at 0° C. for 15 min, the resulting dark red solution was added via syringe to a solution of 0.79 g (4.0 mmol) of N-(ethoxycarbonyl)tropinone (6) in 8 mL of THF at 0° C. and then stirred at room temperature for 4 h (an orange color persisted). The reaction mixture was quenched by adding sat. aq. NaCl (15 mL) and then extracted with ether (25 mL×3). The combined organic extracts were dried over Na₂SO₄. The solid residue obtained after solvent evaporation was loaded onto a short silica gel column (3.5 cm×4 cm) to remove the phosphorous impurities. The product was eluted with ether. After the solvent was evaporated, the product enol ether was obtained as a brown oil which was used in the next step without further purification.

The enol ether intermediate was dissolved in a solution of 12 mL of 2 N HCl and 20 mL of acetonitrile, and stirred at room temperature for 16 h. After removing the acetonitrile on a rotary evaporator, the aqueous solution was extracted with ether (25 mL×3). The combined organic extracts were washed with sat. aq. NaHCO₃ (15 mL×2), sat. aq. NaCl (15 mL) and then dried over Na₂SO₄. After the solution was evaporated to dryness, the residue was purified by chromatography (SiO₂, 10%-20% EtOAc in Hexane as eluent). N-(ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octane-3-carbaldehyde (0.65 g) was obtained as a colorless oil in an approximately 1:1 ratio of endo and exo isomers (77%). ESI-MS m/z 212.1 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 9.53 (s, 1H), 4.54 (br s, 1H), 4.38 (br s, 1H), 4.16 (m, 2H), 2.72 (m, 2H), 2.38 (s, 1H), 2.32 (s, 1H), 2.10 (m, 3H), 1.69 (m, 2H), 1.29 (m, 3H).

Preparation B: Synthesis of bicyclo[3.2.1]octane-2-carbaldehyde

Bicyclo[3.2.1]octane-2-carbaldehyde was prepared using an analogous procedure as for Intermediate 1 from commercially available bicyclo[3.2.1]octan-2-one. The crude products were used in the next step without further purification.

Preparation C: Synthesis of 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde

To a stirred solution of furan (9) (15 mL, 200 mmol) and acrolein (13) (6.7 mL, 100 mmol) in DCM (25 mL) was slowly added AlCl₃ (666 mg, 5 mmol) under argon at −43° C. (dry ice/isopropanol bath). The reaction mixture was stirred at −43° C. under argon for 30 min, and then quenched with sat. aq. K₂CO₃ (50 mL). After the reaction mixture was gradually warmed to room temperature, it was extracted with ether (200 mL×5). The combined ether extracts were washed with sat. aq. K₂CO₃ (200 mL×2) and sat. aq. NaCl (200 mL×2), dried over MgSO₄, filtered, and concentrated to give 2.6 g of oily crude product 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde which was used in the next step without further purification. See references Laszlo, P.; Lucchetti, J. Tetrahedron Lett. 1984, 25, 4387-4388. Moore, J. A., Partain, E. M. III. J. Org. Chem. 1983, 48, 1105-1106. Dauben, W. G.; Krabbenhoft, H. O. J. Am. Chem. Soc. 1976, 98, 1992-1993. Nelson, W. L.; Allen, D. R.; Vincenzi, F. F. J. Med. Chem. 1971, 14, 698-702.

To a stirred solution of crude product 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (2.6 g. 20 mmol) in 95% EtOH (200 mL) was added 10% Pd—C (0.25 g) at room temperature under argon. The mixture was shaken on a Parr hydrogenation apparatus for 4 h at room temperature under 30 psi of hydrogen. After the Pd catalyst was removed by filtration through a Celite pad, the Celite was washed with MeOH (15 mL×2), the combined extracts were concentrated under vacuum to yield 2.5 g of crude 7-oxa-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde as a pale yellow oil, which was used in the next step without further purification.

Preparation D: Synthesis of ethyl 4-formylpiperidine-1-carboxylate

1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H₂O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at ˜0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H₂O, 0.1 NHCl (aq) (×2), saturated brine, then dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. Yield=96%. ¹H-NMR (400 MHz, CDCl₃) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); t_(R)=1.56 min [10-99% CH₃CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₉H₁₇NO₃=188.1; Found 188.0.

A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise, under nitrogen, with a solution of 2.4 eq anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 minutes after the addition was complete, a solution of 1.0 eq ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with H₂O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine, then dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscous amber oil. Yield=90%. ¹H-NMR (400 MHz, CDCl₃) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).

Preparation E: Synthesis of ethyl 4-formyl-4-methylpiperidine-1-carboxylate

Diisopropylamine (3.14 mL; 22.23 mmol; 1.1 eq.) was dissolved in THF (60 mL) and cooled to −78° C. Butyl lithium (2.5 M in hexane; 8.89 mL; 22.23 mmol; 1.1 eq.) was then added and the solution was stirred for 30 minutes at −78° C. Ethyl 1-benzylpiperidine-4-carboxylate (5 g; 20.21 mmol; 1 eq.) was dissolved in THF (40 mL) and added to the LDA solution at −78° C. The solution was stirred at −78° C. for 30 minutes and iodomethane (1.32 mL; 21.22 mmol; 1.05 eq.) was added. The solution was slowly warmed to room temperature and stirred at room temperature for 1 hour. Water (100 mL) was then added to the reaction followed by EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the product (5.0 g, 94% yield) as an oil. The product was analytically pure and used without further purification. LC/MS m/z (M+1) 262.0, Retention time 1.78 minutes; (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.14 (m, 5H), 4.08 (q, J=7.1 Hz, 2H), 3.40 (s, 2H), 2.60-2.57 (m, 2H), 2.08-2.02 (m, 4H), 1.47-1.40 (m, 2H), 1.17 (t, J=7.1 Hz, 3H), 1.10 (s, 3H).

1-Benzyl-4-methylpiperidine-4-carboxylate (5.0 g; 19.15 mmol) was dissolved in Et₂O (50 mL) and cooled to 0° C. LiAlH₄ (1.0 g; 26.3 mmol) was slowly added portion-wise to the solution. After the addition was complete, the solution was slowly warmed to room temperature and stirred for 1 h. The solution was then cooled to 0° C. and slowly quenched with 1N NaOH (6 mL). The resultant white precipitates were filtered and washed with EtOAc (100 mL). The combined organic layers were concentrated under reduced pressure to provide the product (3.9 g, 90% yield) as an oil which was used without further purification. LC/MS m/z M+1 220.0, retention time 0.64 minutes; (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.16 (m, 5H), 3.46 (s, 2H), 3.30 (d, J=3.9 Hz, 2H), 2.51-2.46 (m, 2H), 2.26-2.20 (m, 2H), 1.52-1.45 (m, 3H), 1.30-1.25 (m, 2H), 0.87 (s, 3H).

(1-benzyl-4-methylpiperidin-4-yl)methanol (3.9 g; 17.8 mmol) was dissolved in MeOH (50 mL) and NH₄CO₂H (12.5 g; 178.0 mmol) was added. Pd/C (10% by weight, wet; 5.5 g) was then added and the system was flushed with nitrogen and then with hydrogen. The reaction was stirred at room temperature overnight (18 h) and then filtered through a pad of Celite. The solvent was removed under high vacuum to provide a solid that was a mixture of the amino alcohol and NH₄CO₂H. The crude product (2.4 g as a mixture with NH₄COOH) was used in the next step without further purification. LC/MS m/z (M+1) 130.0, retention time 0.35 min; (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹H NMR (400 MHz, CDCl₃) δ 3.17 (s, 2H), 3.03-2.98 (m, 2H), 2.95-2.88 (m, 2H), 1.64-1.57 (m, 2H), 1.36-1.31 (m, 2H), 0.89 (s, 3H).

(4-methylpiperidin-4-yl)methanol (2.4 g, a mixture of the amino alcohol and NH₄CO₂H) was suspended in DCM (70 mL). Et₃N (5 mL; 37.2 mmol) was then added followed by the drop-wise addition of ethyl chloroformate (1.05 mL, 13 mmol, 1.4 eq.). After 1 hour at room temperature, 1N HCl (70 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (70 mL) and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under high vacuum. The product (1.7 g, 47% yield over 2 steps) is obtained analytically pure as an oil and used without further purification. LC/MS m/z (M+1) 202.2, retention time 1.89 minutes; (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min) ¹H NMR (400 MHz, DMSO-d₆) δ 4.05 (q, J=7.1 Hz, 2H), 3.66 (dt, J=13.6, 4.7 Hz, 2H), 3.32 (s, 2H), 3.11 (t, J=5.2 Hz, 1H), 3.11 (dd, J=23.9, 3.5 Hz, 1H), 1.44-1.37 (m, 3H), 1.26-1.22 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 0.93 (s, 3H).

To a 100 mL round bottom flask was added DCM (30 mL) and oxalyl chloride (0.88 mL; 10.13 mmol). The solution was cooled to −78° C. and treated with DMSO (1.19 mL; 16.88 mmol). The solution was stirred at −78° C. for 20 minutes and then treated with ethyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (1.7 g; 8.44 mmol, dissolved in 10 mL of DCM). The solution was stirred for 30 minutes at −78° C. and then treated with Et₃N (3.53 mL; 25.32 mmol). The solution was stirred at −78° C. for 20 min and then slowly warmed to room temperature and stirred at room temperature for an additional 2 h. The solution was then treated with saturated aqueous NaHCO₃ (50 mL), diluted with DCM (50 mL), and the layers were separated. The organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 1.6 g (95% yield) of the product as an oil which was used without further purification. LC/MS m/z (M+1) 200.0, retention time 2.23 minutes; (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min) ¹H NMR (400 MHz, CDCl₃) δ 9.40 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.66 (dt, J=13.6, 4.7 Hz, 2H), 3.09 (dd, J=10.1, 3.5 Hz, 1H), 3.06 (dd, J=10.2, 3.4 Hz, 1H), 1.86 (dt, J=13.6, 4.4 Hz, 2H), 1.42-1.30 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 1.02 (s, 3H).

Preparation F: Synthesis of benzyl 4-oxotropane-N-carboxylate

Tropinone (10.0 g; 71.84 mmol) was dissolved in DCE (60 mL) and treated drop-wise with 1-chloroethyl chloroformate ACE-Cl (14.5 mL; 19.11 g; 133.7 mmol). The reaction was allowed to stir at room temperature overnight and was then diluted with Et₂O (400 mL) and filtered. The filtrate was concentrated under reduced pressure to provide the crude chloroethyl carbamate. This compound was taken in MeOH (200 mL) and stirred at room temperature for 1 h, then concentrated under reduced pressure (at 55° C.) to provide the crude des-methyltropinone as the HCl salt (tan solid, 11.4 g, 98% yield). The crude material was recrystallized from acetonitrile to furnish the pure product as a white crystalline solid (5 g, 43% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.79 (dd, J=15.0, 6.9 Hz, 2H), 2.09 (m, 2H), 2.40 (d, J=16.7 Hz, 2H), 3.02 (dd, J=17.1, 4.3 Hz, 2H), 4.23 (s, 2H), 10.00 (br s, 2H)

Des-methyl tropinone (5.10 g; 31.55 mmol) was dissolved in CH₂Cl₂ (50 mL) and treated with benzyl chloroformate (4.29 mL; 5.11 g; 29.98 mmol) DIPEA (16.48 mL; 12.23 g; 94.66 mmol) was added drop-wise (exothermic reaction). The resulting clear solution was allowed to stir at room temperature for 30 min and was subsequently diluted with 100 mL CH₂Cl₂. The organic phase was washed with 1 N HCl (2×100 mL), dried on Na₂SO₄ and concentrated to provide the crude product (7.2 g, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.71 (dd, J=15.0, 7.2 Hz, 2H), 2.12 (m, 2H), 2.38 (d, J=15.9 Hz, 2H), 2.67 (m, 2H), 4.62 (s, 2H), 5.22 (s, 2H), 7.38 (m, 5H).

Example 1

To a solution of compound N-Boc Spiroindane 1a (60.0 g, 0.21 mol) in CH₂Cl₂ (1000 mL) was added H₂O (500 mL), TBAB (6.9 g, 0.02 mol) and KOH (3.5 g, 0.06 mol) and followed by addition of KMnO₄ (70.0 g, 0.45 mol) in several portions. After stirring for two days at 35° C., another quantity of KMnO₄ (70.0 g, 0.45 mol) was added and the mixture was continued to stir for 2 days. After Na₂SO₃ (103.0 g, 1.0 mol) was added in portions at 5° C., the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under vacuum. The residue was purified by column chromatography (PE/EtOAc:5/1) to yield 1b (30.0 g, 47.7%). ¹H NMR (CDCl₃) δ: 7.74-7.72 (m, 1H), 7.66-7.64 (m, 1H), 7.62-7.61 (m, 1H), 7.49-7.38 (m, 1H), 4.22-4.20 (m, 2H), 2.89-2.82 (m, 2H), 2.63 (s, 2H), 2.02-1.94 (m, 2H), 1.56-1.52 (m, 2H), 1.49 (s, 9H). MS (ESI) m/z (M+H⁺) 246.0/202.1.

Boc-protected starting material 1b (400.0 mg; 1.33 mmol) was dissolved in CH₂Cl₂ (1.5 mL) and treated with TFA (1.5 mL). The reaction was allowed to stir at room temperature for 1 h and was then quenched by adding H₂O (5 mL) and Et₂O (7 mL). The layers were separated, and the aqueous layer was brought to a basic pH by addition of solid KOH. The resulting emulsion was extracted with Et₂O (3×10 mL). The combined organic extracts were dried on Na₂SO₄ and concentrated to yield the desired product 1c as a colorless oil that solidifies upon standing (220 mg, 82% yield). LC/MS m/z 202.2 [M+H]⁺, retention time 0.72 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min).

Intermediate 1c (40 mg; 0.2 mmol) was suspended in DCE (1 mL) and treated with (1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (31 mg; 0.26 mmol; 1.300 eq.) in DCE (0.5 mL), followed by portion-wise addition of NaBH(OAc)₃ (127 mg; 0.6 mmol) The reaction was allowed to stir at room temperature for 1 h and was then quenched with MeOH (1 mL) and allowed to stir for another 30 min. The crude reaction mixture was purified by HPLC (10-99% CH₃CN gradient with 0.03% TFA, 15 min) to provide the purified compound no. 237. LC/MS m/z 308.2 [M+H]⁺, retention time 2.08 (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min). ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (br s, 1H), 7.81-7.77 (m, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.59 (d, J=7.8 Hz, 7.53-7.49 (m, 1H), 6.27 (dd, J=5.7, 3.0 Hz, 1H), 6.05 (dd, J=5.7, 2.8 Hz, 1H), 3.60 (t, J=12.7 Hz, 3H), 3.11-2.90 (m, 4H), 2.85-2.74 (m, 4H), 2.29 (t, J=13.0 Hz, 2H), 2.05-1.99 (m, 1H), 1.76 (d, J=14.2 Hz, 2H), 1.39-1.35 (m, 1H), 1.29 (d, J=8.2 Hz, 1H), 0.71-0.66 (m, 1H).

Example 2

1.0 eq of the Boc-protected spiroindanone 2a (2.06 g, 6.84 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and added drop-wise, under nitrogen, to an ice-cold (˜0° C.) suspension of 2.2 eq sodium hydride (600 mg, 60% dispersion in mineral oil, 15.0 mmol) in anhydrous tetrahydrofuran (10 mL). A solution of 10.0 eq iodomethane (9.71 g, 68.4 mmol) in anhydrous tetrahydrofuran (5 mL) was then added drop-wise over 20 min. The reaction was warmed to room temperature and stirred for 2 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and slowly treated with H₂O (25 mL). The product was extracted with ethyl acetate (2×50 mL) and the pooled extracts washed with saturated sodium bicarbonate and saturated brine, then dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to afford 2.41 g crude product 2b as a viscous, pale yellow oil. Yield=˜100%. ¹H-NMR (400 MHz, acetone-d₆) δ 7.90 (d, J=6.8 Hz, 1H), 7.71 (m, 2H), 7.49 (t, J=7.4 Hz, 1H), 3.75 (m, 2H), 3.56 (br m, 2H), 1.89 (m, 2H), 1.64 (br m, 2H), 1.48 (s, 9H), 1.12 (s, 6H); t_(R)=3.50 min [10-99% CH₃CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₂₀H₂₇NO₃=330.2; Found 330.2.

The gem-dimethyl spiroindanone 2b (379 mg, 1.15 mmol) was dissolved in dichloromethane (2.5 mL), cooled in an ice-H20 bath and treated slowly with trifluoroacetic acid (2.5 mL). The reaction was stirred for 30 min at ˜0° C., then concentrated under reduced pressure. The oil obtained was dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was treated with 1.0 N NaOH (5 mL) and extracted with ethyl acetate (2×30 mL). The pooled extracts were washed with H2O and saturated brine, then dried (Na₂SO₄) and filtered. The filtrate was concentrated in vacuo to afford 210 mg of the crude free base 2c as a colorless semi-solid. Yield=80%. t_(R)=1.52 min [10-99% CH₃CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)+m/z for C₁₅H₁₉NO=230.2; Found 230.2

The crude free base 2c (53 mg, 0.23 mmol) was dissolved in anhydrous 1,2-dichloroethane (1.0 mL) and treated with N-(carbethoxy)-4-tropinone (55 mg, 0.28 mmol), followed by titanium tetraisopropoxide (202 μL, 196 mg, 0.69 mmol). The vial was flushed with nitrogen and stirred at room temperature for 2.5 days. The reaction was diluted with methanol (1.0 mL), cooled in an ice-H₂O bath and treated with sodium borohydride (17 mg, 0.46 mmol). The reaction was warmed to room temperature and stirred thereafter for 30 min. The reaction was then quenched with 1.0 N NaOH (750 μL), diluted with methanol (1.5 mL) and stirred at room temperature for 10 min. The suspension obtained was centrifuged (3K rpm, 10 min) and the supernatant concentrated under reduced pressure. The residue obtained was dissolved in DMSO:methanol (1.5 mL, 1:1 v/v), filtered, and purified by reverse-phase HPLC (2-40% CH₃CN gradient over 10 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected) to produce the compound no. 277 as a TFA salt. t_(R)=2.12 min [10-99% CH₃CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₂₅H₃₄N₂O₃=411.3; Found 411.2.

Example 3

The starting Spiroindane 3a (45 mg, 0.2 mmol) was suspended in DCE (1 mL) and treated with (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (25 mg, 0.2 mmol) in DCE, followed by the addition of NaBH(OAc)₃ (63 mg, 0.3 mmol). The reaction was allowed to stir at room temperature for 1 h and was then quenched with MeOH (0.5 mL) and allowed to stir for another 30 min (until gas evolution stopped). The crude reaction mixture was filtered, then purified by HPLC (10-99% CH₃CN/0.05% TFA gradient) to yield compound no. 312. LC/MS m/z 294.4 [M+H]⁺, retention time 2.33 min (RP—C₁₈, 10-99% CH₃CN/0.05% TFA); ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (br s, 1H), 7.25-7.17 (m, 3H), 7.13 (d, J=6.9 Hz, 1H), 6.27-6.26 (m, 1H), 6.06-6.04 (m, 1H), 3.56-3.40 (m, 3H), 3.11-3.03 (m, 2H), 2.98-2.78 (m, 6H), 2.09-1.98 (m, 5H), 1.67 (d, J=13.9 Hz, 2H), 1.36 (t, J=8.0 Hz, 1H), 1.29 (d, J=8.2 Hz, 1H), 0.70-0.66 (m, 1H).

Example 4

To a solution of 2-amino-4-chloro-phenol 4a (50 g, 0.35 mol) in HCl (2.5 mol, 500 mL) was added drop-wise a solution of sodium nitrite (25.25 g, 0.35 mol) in water (50 mL) at 0° C. The mixture was stirred at this temperature for 30 min. Then a cooled solution of KI (70 g, 0.42 mol) in H₂O (100 mL) was slowly added at 0° C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and the separated aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic fraction was washed with Na₂S₂O₃ (10%, 100 mL), water (100 mL×2) and brine (200 mL), dried over Na₂SO₄ and concentrated to dryness. The residue was purified by column on silica gel to afford 4-chloro-2-iodo-phenol 4b as a yellow solid (46 g, yield 51.7%). ¹H NMR (400 MHz, CDCl₃): δ 7.67 (d, J=2.4 Hz, 1H), 7.21 (dd, J=2.4, 8.4, Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 5.33 (s, 1H).

To a solution of 4-chloro-2-iodo-phenol 4b (20.32 g, 0.08 mol), (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08 mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) was added DEAD (17.4 g, 0.09 mol) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was basified by Na₂CO₃ solution (10% 100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL×2) and brine (200 mL), dried over Na₂SO₄, concentrated to dryness. The residue was purified by column on silica gel to afford 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4c (30 g, 86%). ¹H NMR (400 MHz, CDCl₃): δ 7.73 (d, J=2.4 Hz, 1H), 7.22-7.38 (m, 6H), 6.70 (d, J=8.8 Hz, 1H), 5.82 (s, 1H), 4.43 (s, 2H), 3.63 (s, 2H), 3.05 (s, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.28 (s, 2H).

To a refluxing solution of 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4c (26.7 g, 0.06 mol) and AIBN (0.05 g, 0.003 mol) in dry benzene was added a solution of Bu₃SnH (40 g, 0.137 mol) in benzene (100 mL) over 1 h under nitrogen atmosphere. After addition, the mixture was refluxed for 3 hr and additional AIBN (0.5 g, 0.003 mol) and Bu₃SnH (20 g, 0.68 mol) were added. After refluxing for 4 hr, the mixture was concentrated to dryness, and EtOAc (100 mL) and HCl (10%, 40 mL) were added. The precipitate was filtered and washed with petroleum ether to give 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) as its HCl salt, which was basified by NaHCO₃ solution to give 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) 4d (13 g, 68%).

To a solution of 2,3-dihydro-1′-benzyl-5-chlorospiro(benzofuran-3,4′-piperidine) 4d (13 g, 0.04 mol) in CH₂Cl₂ (130 mL) was added drop-wise 1-chloroethyl chloroformate (7.2 g, 0.05 mol). The mixture was stirred for 3 hr at room temperature and then concentrated to dryness. The residue was dissolved in CH₃OH (30 mL) and the solution was heated to reflux for 30 min. After removing of the solvent, ether was added. The resulted solid was filtered and washed with ether to the debenzylated product 4e as the HCl salt (5.5 g, yield 48%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.08 (br s, 1H), 7.16-7.19 (m, 2H), 6.82 (d, J=8.4 Hz, 1H), 4.50 (s, 2H), 3.25-9.29 (m, 2H), 2.98-2.92 (m, 2H), 2.12-2.05 (m, 2H), 1.83-1.8 (m, 2H).

The chloro-dihydrobenzofuran spiro amine 4e (3.18 mmol) was dissolved in anhydrous DCE (15 mL) and treated with triethylamine (322 mg, 3.18 mmol), followed by (+)-2-norcamphor (421 mg, 3.82 mmol), acetic acid (382 mg, 6.36 mmol) and NaBH(OAc)₃ (1.35 g, 6.37 mmol). The reaction was stirred vigorously under nitrogen at room temperature for ˜36 hours. The reaction was quenched with methanol (15 mL) and stirred vigorously for 10 min at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue obtained dissolved in a mixture of DMSO:CH₃OH (20 mL, 1:3 v/v). The solution was filtered and purified by reverse-phase HPLC (2-99% CH₃CN/0.05% TFA, 35 mL/min). The combined pure fractions were concentrated under reduced pressure until ˜25 mL of solvent remained. The suspension was treated with 1 N NaOH (25 mL) and extracted with CH₂Cl₂ (3×50 mL). The combined organic extracts were washed with H₂O, saturated brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford 522 mg pure free base (1.64 mmol) as a crystalline white solid. The free base was readily dissolved in anhydrous diethyl ether (10 mL) and treated with 1.0 eq 1 N ethereal HCl (1.7 mL). The thick, gelatinous suspension obtained was cooled in an ice/H₂O bath for 1 hour, filtered, rinsed with Et₂O (3×10 mL), and dried overnight under reduced pressure to yield compound no. 1 as a fine white powder. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.1 (br s, 1H), 7.77 (d, J=2.2 Hz, 0.2H), 7.21 (dd, J=2.3 Hz, 8.5 Hz, 1H), 7.08 (d, J=2.3 Hz, 0.8H), 6.85 (d, J=8.5 Hz, 0.8H), 6.84 (d, J=8.5 Hz, 0.2H), 4.52 (s, 1.6H), 4.45 (s, 0.4H), 3.41 (m, 1.8H), 3.24 (m, 0.8H), 3.01 (br m, 1.6H), 2.63 (br m, 2H), 2.44 (m, 0.9H), 2.27 (br s, 1.1H), 1.86 (br m, 4H), 1.51 (br m, 3.3H), 1.39 (br m, 2.7H), 1.24 (br m, 0.7H); LC/MS m/z 318.0 [M+H]⁺, retention time 2.14 min (RP—C₁₈, 10-99% CH₃CN/0.05% TFA).

Example 5

The starting material 5a (54 mg, 0.2 mmol, 1.0 eq) was suspended in DCE (1 mL) and treated with (1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (31 mg, 0.26 mmol, 1.3 eq) in DCE (0.5 mL), followed by portion-wise addition of NaBH(OAc)₃ (127 mg, 0.6 mmol). The reaction was allowed to stir at room temperature for 3 h and was then quenched with MeOH (2 mL) and allowed to stir for another hour (until gas evolution stopped). The reaction mixture was then diluted with H₂O (5 mL) and extracted with Et₂O (10 mL). The organic layer was treated with 1 N HCl (5 mL) and formation of an insoluble precipitate was observed. The biphasic emulsion was filtered, and the white precipitate was washed with Et₂O (3×5 mL) and hexanes (2×10 mL) and dried under vacuum to provide the pure HCl salt of compound no. 64 as white shiny platelets. LC/MS m/z 344.0 [M+H]⁺, retention time 2.56 min (RP—C₁₈, 10-99% CH₃CN/0.05% TFA). ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.18 (q, J=2.8 Hz, 1H), 6.02 (q, J=2.7 Hz, 1H), 4.05-4.03 (m, 2H), 3.37-3.32 (m, 2H), 3.08-2.97 (m, 3H), 2.85-2.77 (m, 2H), 2.72-2.65 (m, 1H), 2.49-2.45 (m, 3H), 1.98-1.90 (m, 3H), 1.72-1.70 (m, 2H), 1.26 (dd, J=33.4, 7.3 Hz, 2H), 0.63 (d, J=10.5 Hz, 1H).

Example 6

The fluoroindoline 6a (1.22 g; 4.0 mmol) was suspended in DCE (10 mL) and cooled to −30° C. A solution of (1R,2R,4R)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (635 mg; 5.2 mmol) in dry DCE (2 mL) was added, followed by portion-wise addition of NaBH(OAc)₃ (1.18 g; 5.6 mmol). The reaction was stirred at −30° C. under nitrogen for 90 min then at room temperature until complete consumption of starting material was observed by LC/MS (30 h). The reaction was quenched with MeOH (10 mL) and allowed to stir vigorously for 30 min (until gas evolution stopped). The reaction was diluted with 1N HCl (80 mL) and Et₂O (50 mL). Formation of a white precipitate can be observed as the HCl salt of the desired product is insoluble in both phases. The biphasic mixture was filtered, and the precipitate was washed with Et₂O (2×20 mL) and hexanes (2×30 mL) and dried under high vacuum to provide the product 6b as the corresponding HCl salt (white powder, 1.41 g, 78.5% yield).

The HCl salt 6b (1.4 g; 3.1 mmol) was dissolved in CH₂Cl₂ (10 mL) and TFA (10 mL) was added. The reaction mixture was allowed to stir at room temperature for 1 h. The reaction was quenched with water (100 mL) and diluted with hexanes (40 mL) and Et₂O (50 mL). The layers were separated, and the organic layer was extracted with H₂O (2×100 mL). The combined aqueous layers were washed with Et₂O (50 mL) then neutralized with solid KOH (under dry-ice bath cooling) until formation of an oily suspension was observed. The suspension was extracted with EtOAc (3×100 mL) and CH₂Cl₂ (100 mL), and the combined organic extracts were dried over Na₂SO₄ and concentrated to provide the crude product as a light brown oil. The amine was dissolved in 15 mL Et₂O and treated with 2 N HCl in ether (1.5 mL, 3.0 mmol, 0.96 eq). After 20 min of stirring the resulting precipitate was vacuum filtered under a nitrogen atmosphere, washed with 50 mL Et₂O, 30 mL Et₂O:CH₃CN (5:1) and 40 mL hexanes and dried under high vacuum to provide the HCl salt of compound no. 147 as an off-white powder. LC/MS m/z 313.30 [M+H]⁺, retention time 1.73 min (RP—C₁₈, 10-99% CH₃CN/0.05% TFA). ¹H NMR (400 MHz, MeOD) δ 0.83 (ddd, J=5.8, 2.6 Hz, 1H), 1.41 (d, J=8.4 Hz, 1H), 1.54 (m, 1H), 2.01 (s, 1H), 2.05 (d, J=3.9 Hz, 1H), 2.15 (ddd, J=6.1, 3.1 Hz, 1H), 2.23 (m, 2H), 2.60 (m, 1H), 2.86 (dd, J=13.0, 7.4 Hz, 1H), 2.93 (s, 1H), 3.11 (m, 4H), 3.66 (m, 4H), 6.09 (d, J=2.8 Hz, 1H), 6.33 (d, J=3.0 Hz, 1H), 6.90 (m, 3H).

Example 7

Starting material 7a hydrochloride (2.17 g, 6.40 mmol) was suspended in anhydrous DCE (30 mL) and treated with triethylamine (648 mg, 6.40 mmol), followed by (−)-2-norcamphor (706 mg, 6.40 mmol), acetic acid (770 mg, 12.8 mmol) and NaBH(OAc)₃ (2.72 g, 12.8 mmol). The reaction was stirred vigorously under nitrogen at room temperature for ˜72 h (˜77% conversion by LC/MS at 220 nm). The reaction was quenched with methanol (10 mL) and stirred vigorously for 10 min at room temperature. The reaction mixture was then concentrated under reduced pressure and the residue obtained dissolved in a 1:1 mixture of DMSO:CH₃OH (30 mL). The mixture was centrifuged (3,000 rpm, 10 min) and the supernatant filtered and purified by reverse-phase HPLC (10-99% CH₃CN/0.05% TFA, 50 mL/min). The combined pure fractions were concentrated under reduced pressure to afford 2.25 g of the N-Boc intermediate 7b (isolated as the TFA salt) as an off-white solid (69% isolated yield, Purity=99+%). LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 397.4 [M+H]⁺, retention time 2.70 min.

The N-Boc intermediate 7b (2.25 g, 4.41 mmol) was dissolved in dichloromethane (25 mL) and slowly treated with trifluoroacetic acid (15 mL). The reaction was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The oil obtained was slowly treated with 1 N NaOH (100 mL) and extracted with CH₂Cl₂ (2×75 mL). The combined extracts were washed with H₂O, saturated brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford 1.147 g (3.87 mmol) free base as a yellow oil. The free base was dissolved in a minimal volume of anhydrous diethyl ether and treated with 0.95 eq 1 N ethereal HCl. The suspension was cooled in an ice/H₂O bath for 1 h, filtered, rinsed with Et₂O, and dried overnight under reduced pressure to yield 1.213 g (57% yield) of the desired product 7c as a fine, off-white to very pale yellow powder. LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 297.2 [M+H]⁺, retention time 1.72 min.

The deprotected amine HCl salt 7c (33 mg, 0.10 mmol) was suspended in anhydrous CH₃CN (1.0 mL) and treated with triethylamine (20 mg, 0.20 mmol), followed by methanesulfonyl chloride (14 mg, 0.12 mmol). The reaction was stirred at room temperature for 10 min, then quenched with DMSO:CH₃OH (1.0 mL, 1:1 v/v) and centrifuged (4000 rpm, 7 min). The supernatant was filtered and purified by reverse-phase HPLC (2-99% CH₃CN, 50 mL/min, 2.0 mL injected) to yield the desired compound no. 231 as the TFA salt. LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 375.0 [M+H]⁺, retention time 2.08 min.

Example 8

Boc-protected fluoroindoline 8a (1.41 g; 4.11 mmol) and benzyl 4-oxotropane-N-carboxylate (1.07 g; 4.11 mmol) were dissolved in a mixture of DCE (5 mL) and DME (5 mL) and placed under a nitrogen atmosphere. TEA (0.57 mL; 0.42 g; 4.11 mmol) was added, followed by Ti(OiPr)₄ (1.21 mL; 1.17 g; 4.11 mmol) and the reaction was allowed to stir at room temperature for 60 h. The reaction mixture was diluted with 30 mL MeOH and cooled to −40° C. to −50° C. NaBH₄ (0.6 g; 13.45 mmol) was added portion-wise over 30 min and the reaction was allowed to stir at −40° C. to −20° C. until bubbling subsided (3 h), then warmed slowly to room temperature and was stirred for 2 h. The sticky suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL) and Et₂O (3×50 mL). The filtrate was separated into the corresponding layers, and the aqueous layer was extracted with Et₂O (2×50 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated to provide the crude product as a white foam. This material was dissolved in Et₂O (400 mL) and treated with 1 N aq. HCl (500 mL) and the mixture was vigorously stirred for 20 min. The resulting biphasic suspension was filtered, the precipitate was washed with HCl 1N (2×30 mL), H₂O (2×30 mL) and Et₂O (3×30 mL) and dried. To remove the unreacted starting material by conversion to the corresponding ethyl carbamate, the crude HCl salt was suspended in acetonitrile (10 mL) and treated sequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL). After 10 min, the mixture was diluted with Et₂O (300 mL) and poured onto 1 N aq HCl (300 mL). The biphasic suspension was filtered, and the precipitate was washed with HCl 1N (2×30 mL), H₂O (2×30 mL) and Et₂O (3×30 mL) and dried to provide the desired product 8b hydrochloride salt. LC/MS m/z [M+H]⁺550.4 retention time 2.93 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min).

Cbz-protected starting material 8b (1.140 g; 1.945 mmol) was dissolved in methanol (20 mL) and treated with 10% wet Pd/C (1.14 g) and NH₄COOH (2.45 g; 38.9 mmol) The mixture was allowed to stir vigorously overnight under an empty balloon (for venting). LC/MS analysis shows complete conversion to the desired product. The reaction mixture was filtered through a pad of Celite under a nitrogen atmosphere, and the filter cake was rinsed with methanol (4×30 mL). The filtrate was concentrated to provide the crude product, which was taken up in a mixture of EtOAc (100 mL) and NaHCO₃ sat. (100 mL). The layers were separated, the aqueous layer was extracted with EtOAc (2×100 mL), Et₂O (100 mL), and CH₂Cl₂ (2×100 mL). The combined organic layers were dried over Na₂SO₄ and concentrated to provide the crude product 8c as a white foam (707 mg, 87% yield). LC/MS m/z 416.4 [M+H]⁺, retention time 2.26 (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min)

Compound 8c (250.0 mg; 0.60 mmol) was dissolved in DCM (15 mL) and treated sequentially with methoxyethyl chloroformate (138.4 uL; 166.1 mg; 1.203 mmol) and TEA (401.7 uL; 291.7 mg; 2.89 mmol). After 10 min, the reaction mixture was diluted with DCM (30 mL) and washed with saturated NaHCO₃ solution (30 mL). The aqueous layer was extracted with DCM (30 mL) and the combined organic extracts were dried on Na₂SO₄ and concentrated to provide the desired product 8d which was taken to the next step without further purification. LC/MS m/z 518.0 [M+H]⁺, retention time 2.43 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min).

Intermediate 8d was dissolved in a mixture of DCM (15 mL) and TFA (20 mL) and allowed to stir at room temperature for 2 h. The reaction mixture was concentrated, dissolved in water (20 mL) and the pH was adjusted to basic by portion-wise addition of solid KOH. The resulting suspension was extracted with DCM (3×30 mL) and Et₂O (30 mL) and the organic extracts were dried over Na₂SO₄, and then concentrated to provide the free base of the desired product. The material was dissolved in Et₂O (20 mL) and treated with excess 1N HCl in ether (2 mL). The resulting suspension was filtered under nitrogen and the filtrate was washed with Et₂O (3×10 mL) and dried under vacuum to provide the desired product 8e as an off white solid (232 mg, 85% yield over 2 steps). LC/MS m/z 418.2 [M+H]⁺, retention time 1.16 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min).

Intermediate 8e (230.0 mg; 0.51 mmol) was suspended in DCM (15 mL) and treated sequentially with dimethyl carbamoyl chloride (931.3 uL; 1089.7 mg; 10.13 mmol) and TEA (704.8 uL; 511.70 mg; 5.07 mmol). The reaction was allowed to stir overnight at room temperature, and then the mixture was diluted with DCM (30 mL) and washed with saturated NaHCO₃ solution (30 mL). The aqueous layer was extracted with DCM (30 mL) and the combined organic extracts were dried over Na₂SO₄ and concentrated to provide the free base of the desired product. This material was dissolved in Et₂O (20 mL) and treated with excess 1N HCl in ether (3 mL). The resulting suspension was filtered under nitrogen and the filtrate was washed with Et₂O (3×10 mL) and dried under vacuum to provide the desired compound no. 119 as an off-white solid. LC/MS m/z 489.4 [M+H]⁺, retention time 2.20 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min) ¹H NMR (400 MHz, DMSO-d₆) δ 1.66 (d, J=7.0 Hz, 2H), 1.82 (s, 4H), 1.86 (s, 2H), 1.92 (s, 2H), 2.07 (s, 2H), 2.22 (t, J=12.1 Hz, 2H), 2.87 (s, 6H), 3.05 (q, J=11.1 Hz, 2H), 3.28 (s, 3H), 3.53 (m, 4H), 3.73 (m, 1H), 4.15 (d, J=4.4 Hz, 2H), 4.27 (s, 2H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (m, 2H), 10.41 (s, 1H).

Example 9

Example 9: Bromo-spiroindoline 9a (1.5 g, 4.08 mmol) was dissolved in anhydrous dichloromethane (20 mL) and cooled to 0° C. To the rapidly stirring solution was added acetyl chloride (0.481 g, 6.13 mmol) followed by triethylamine (0.853 mL, 6.13 mmol). The reaction mixture was stirred at room temperature for 1 h. Then mixture was concentrated under reduced pressure to afford desired product 9b as viscous pale yellow oil and carried to the next step without further purification. LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 411.0 [M+H]⁺, retention time 3.39 min.

The intermediate 9b was dissolved in 10 mL of dichloromethane and treated with trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The oil obtained was re-dissolved in acetonitrile, re-concentrated under reduced pressure, treated with 2 N NaOH (25 mL) and extracted with dichloromethane (2×50 mL). The combined extracts were washed with saturated NaHCO₃, saturated brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford crude free base 9c as a pale yellow oil. LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 309.7 [M+H]⁺, retention time 2.07 min.

Intermediate 9c (1.260 g, 4.08 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) and treated with 2 eq of 1-carbethoxy-4-piperidone (1.393 g, 8.16 mmol), followed by glacial acetic acid (0.490 g, 8.16 mmol) and sodium triacetoxyborohydride (1.721 g, 8.16 mmol). The reaction was stirred at room temperature under nitrogen for 48 h. The reaction was diluted with dichloromethane (50 mL), quenched with 1.0 N NaOH (20 mL) and stirred vigorously at room temperature for 30 min. The layers were separated and the aqueous layer extracted with DCM (2×20 mL). The pooled organic layers were washed with H₂O (20 mL), brine (20 mL), then dried over Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to afford 1.8 g crude product 9d as pale yellow oil (˜95% yield). An analytical sample was subjected to reverse-phase HPLC purification (2-50% CH₃CN gradient over 13 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected). The remainder of the material was taken to the next step without purification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 4.13 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.54-3.46 (m, 3H), 3.16 (q, J=11.0 Hz, 2H), 2.83 (bs, 2H), 2.21 (s, 3H), 2.17-2.07 (m, 4H), 1.93 (d, J=15.6 Hz, 2H), 1.66-1.55 (m, 2H), 1.20 (t, J=7.0 Hz, 3H). LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min) m/z 467.2 [M+H]⁺, retention time 1.97 min.

Product 9d (46.4 mg, 0.1 mmol) was mixed with 4-methylphenyl boronic acid (14 mg, 0.1 mmol) in 1 mL of CH₃CN and 1 mL of 2 M aq. Na₂CO₃. The microwave tube was purged with N₂ and 7 mg (10 mol %) of PdCl₂(dppf) was added and tube was again purged with N₂, then sealed and microwaved for 20 min at 150° C. After reaction was complete, organic layer was separated, filtered trough silica gel plug, concentrated and was subjected to reverse-phase HPLC purification (RP—C₁₈, 2-50% CH₃CN/0.1% aq. TFA gradient over 13 min, 35 mL/min) to yield compound no. 58. ¹H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.39 (d, J=1.5 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 4.14 (s, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.58 (m, 3H), 3.19 (q, J=11.1 Hz, 2H), 2.85 (bs, 2H), 2.34 (s, 3H), 2.29-2.23 (m, 5H), 2.09 (d, J=12.9 Hz, 2H), 1.96 (d, J=13.9 Hz, 2H), 1.67-1.57 (m, 2H), 1.20 (t, J=7.1 Hz, 3H). LC/MS (RP—C₁₈, 10-99% CH₃CN/0.05% TFA gradient over 5 min): m/z 476.2 [M+H]⁺, retention time 2.36 min.

Example 10

1.0 eq of the amine hydrochloride 10a (416 mg, 1.46 mmol) was suspended in anhydrous 1,2-dichloroethane:1,2-dimethoxyethane (6.0 mL, 1:1 v/v) and treated with 1.0 eq triethylamine (148 mg), followed by 1.5 eq tert-butyl 4-oxoazepane-1-carboxylate (467 mg, 2.19 mmol) and 3.0 eq titanium tetraisopropoxide (1.3 mL, 1.26 g, 4.4 mmol). The reaction vial was flushed with nitrogen and stirred at room temperature for 3 days. The reaction was diluted with methanol (6.0 mL), cooled in an ice-H₂O bath and treated with sodium borohydride (110 mg, 2.92 mmol). The reaction was slowly warmed to room temperature and stirred thereafter for 90 min. The reaction was then further diluted with methanol (10 mL), quenched with 1.0 N NaOH (5.0 mL) and stirred vigorously at room temperature for 10 min. The suspension obtained was centrifuged (3K rpm, 10 min) and the supernatant concentrated under reduced pressure. The residue obtained was dissolved in dichloromethane (75 mL) and washed successively with H₂O, saturated sodium bicarbonate, and saturated brine, then dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to afford 704 mg crude product 10b as a viscous, pale yellow oil. The crude product was used in the next step without further purification. t_(R)=2.14 min [10-99% CH₃CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₂₅H₃₆FN₃O₃=446.3; Found 446.4.

The Boc-protected amine 10b (573 mg) was dissolved in dichloromethane (5 mL), cooled in an ice-H₂O bath and treated slowly with ice-cold trifluoroacetic acid (5 mL). The reaction was stirred at ˜0° C. for 1 h, then concentrated under reduced pressure. The oil obtained was dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was dissolved in methanol (6.0 mL) and purified by reverse-phase HPLC (2-25% CH₃CN/0.1% TFA gradient over 10 min, 6×1.0 mL injected, 35 mL/min). The combined pure fractions were concentrated in vacuo to afford 291 mg amine 10c as the di-TFA salt, as a viscous, colorless oil. Yield (over 2 steps)=35%. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.83 (br s, 1H), 8.74 (br s, 2H), 8.06 (dd, J=8.8 Hz, 5.0 Hz, 1H), 7.06 (br m, 1H), 6.97 (br m, 1H), 4.12 (s, 2H), 3.59 (br s, 1H), 3.13 (br m, 6H), 2.36 (m, 1H), 2.20 (s, 3H), 2.13 (m, 5H), 1.89 (m, 5H), 1.71 (m, 1H); t_(R)=1.06 min [10-99% CH₃CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₂₀H₂₈FN₃O=346.2; Found 346.0.

Deprotected amine 10c (46 mg, 0.080 mmol, di-TFA salt) was dissolved in anhydrous acetonitrile (750 μL) and treated with 3.0 eq triethylamine (24 mg, 0.24 mmol). The mixture was then treated with ethyl chloroformate (9 μL, 10 mg, 0.096 mmol) and stirred at room temperature for 30 min. The reaction was quenched with methanol (500 μL) and purified by reverse-phase HPLC to provide compound no. 308 (2-40% CH₃CN/0.1% TFA gradient over 10 min, 1.0 mL injected, 35 mL/min) t_(R)=1.90 min [10-99% CH₃CN gradient over 5 min with 0.1% TFA (aq)]; Theoretical (M+H)⁺ m/z for C₂₃H₃₂FN₃O₃=418.2; Found 418.4.

Example 11

Spiroindoline 11a (300.0 mg; 1.21 mmol) and 4-oxocyclohexane spirodioxolane (283.1 mg; 1.81 mmol) were dissolved in DCE (5 mL). After 10 min, NaBH(OAc)₃ (512.1 mg; 2.42 mmol) was added, followed by AcOH (69.7 uL; 72.5 mg; 1.208 mmol) and the mixture was allowed to stir at room temperature for 75 h. The reaction was quenched by adding MeOH (10 mL) and was allowed to stir for 24 h. The resulting suspension was diluted with DCM (30 mL) and NaOH 1 N (5 mL) was added. The layers were separated, and the aqueous layer was extracted with DCM (3×30 mL). The combined organic extracts were dried on Na₂SO₄ and concentrated. The white solid residue was suspended in ether, the ethereal suspension was filtered and the precipitate was washed with ether (3×20 mL) and dried to provide the acetate salt of the desired product 11b (400 mg, 74% yield). The material was used for the next step without further purification. LC/MS m/z 389.2 [M+H]⁺, retention time 1.73 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min) ¹H NMR (400 MHz, DMSO-d₆) δ 1.49 (m, 4H), 1.60 (d, J=13.0 Hz, 2H), 1.72 (d, J=9.4 Hz, 4H), 1.81 (td, J=13.4, 2.5 Hz, 2H), 2.19 (s, 3H), 2.28 (t, J=11.5 Hz, 2H), 2.37 (m, 1H), 2.80 (d, J=11.5 Hz, 2H), 3.85 (t, J=2.3 Hz, 4H), 3.95 (s, 2H), 6.97 (td, J=8.3, 1.8 Hz, 1H), 7.18 (dd, J=8.8, 2.7 Hz, 1H), 8.02 (dd, J=8.8, 5.0 Hz, 1H)

The ketal 11b (350.0 mg; 0.82 mmol) was dissolved in 80% aq. acetic acid (20 mL) and the solution was refluxed overnight. LC/MS analysis shows complete deprotection of the ketal, along with some deacetylation of the indoline nitrogen. The reaction mixture was diluted with water (20 mL), cooled on an ice bath and neutralized by addition of solid KOH. The resulting suspension was filtered and the precipitate was washed with water (3×10 mL) and dried to provide the crude product as a tan powder. This material was dissolved in DCM (10 mL) and treated with excess AcCl (1 mL) and triethylamine (1 mL). After stirring at room temperature for 3 h, the mixture was diluted with DCM (30 mL) and washed with saturated NaHCO₃. The organic layer was dried on Na₂SO₄ and concentrated to provide the product 11c as a yellow oil (253 mg, 89% yield), which was used for the next step without further purification. LC/MS m/z 345.0 [M+H]⁺, retention time 1.43 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min); ¹H NMR (400 MHz, CDCl₃) δ 1.68 (d, J=13.3 Hz, 2H), 1.82 (m, 2H), 1.91 (m, 2H), 2.07 (m, 2H), 2.18 (s, 3H), 2.29 (m, 6H), 2.45 (m, 2H), 2.78 (t, J=9.5 Hz, 1H), 2.97 (d, J=11.6 Hz, 2H), 3.81 (s, 2H) 6.88 (m, 2H), 8.16 (dd, J=8.5, 4.8 Hz, 1H).

The crude ketone 11c (100.0 mg; 0.29 mmol) was dissolved in pyridine (1 mL) and treated with O-ethyl hydroxylamine hydrochloride (21.3 mg; 0.35 mmol). The vial was sealed and heated to 60° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was dissolved in DMSO (2 mL) and the product oxime compound no. 86 purified by reverse phase HPLC (2-99% CH₃CN—H₂O gradient with 0.03% TFA, 15 min. run). LC/MS m/z 388.4 [M+H]⁺, retention time 1.87 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min); ¹H NMR (free base, 400 MHz, CDCl₃) δ 1.25 (t, J=7.0 Hz, 3H), 1.55 (m, 2H), 1.71 (d, J=13.1 Hz, 2H), 1.94 (m, 5H), 2.14 (m, 1H), 2.25 (s, 3H), 2.30 (td, J=11.9, 5.6 Hz, 2H), 2.50 (d, J=14.3 Hz, 1H), 2.62 (t, J=9.6 Hz, 1H), 2.94 (d, J=11.8 Hz, 2H), 3.25 (d, J=14.7 Hz, 1H), 3.86 (s, 2H), 4.07 (q, J=7.0 Hz, 2H), 6.88 (m, 2H), 8.16 (dd, J=8.5, 4.8 Hz, 1H).

Example 12

The N-Boc protected indanone 12a (6.5 g, 21.6 mmol), (S)-1-phenylethanamine (2.875 g, 23.72 mmol, 1.1 eq), and anhydrous ZnCl₂ (88 mg, 0.647 mmol, 0.03 eq) were brought up in 35 mL dry toluene in a 100-mL flask under N₂ atmosphere. The flask was fitted with a Dean-Stark trap and reflux condenser for the removal of water. The reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled, diluted with EtOAc (200 mL), and washed with 0.1 N NaOH (2×30 mL), 20% saturated NH₄Cl (1×100 mL), and brine (1×100 mL). The organic layer was then dried over Na₂SO₄, filtered, and dried down to afford imine (S)-12b as a light orange solid. LC/MS analysis of the crude product indicated complete conversion to the desired product. LC/MS (10-99%) m/z 405.2 [M+H]⁺, retention time 2.76 min.

The crude imine (S)-12b (21.6 mmol) was dissolved in anhydrous MeOH (30 mL) and cooled to −40° C. under N₂ atmosphere. NaBH₄ (816 mg, 21.6 mmol, 1.0 eq) was added in one portion. The reaction mixture was allowed to warm to −20° C. over 2 h, then warmed to −5° C. for 3 h. The reaction mixture was then diluted with EtOAc (200 mL), then washed with 50% saturated NaHCO₃ (100 mL), water (2×100 mL), and brine (100 mL). The organic layer was dried over Na₂SO₄, filtered, and dried down to yield (S,S)-12c as a colorless oil. The oil was brought up in anhydrous diethyl ether, and 1 eq of ethereal HCl was added to precipitate the product as a fine white solid. The solid was filtered, washed with ether (100 mL), and dried under vacuum to obtain 7.2 of (S,S)-12c HCl salt as a white powder (75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (m, 1H), 9.49 (m, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.1 Hz, 2H), 7.29-7.47 (m, 6H), 4.91 (m, 1H), 4.62 (m, 1H), 3.94 (m, 2H), 2.87 (bs, 2H), 2.62 (dd, J=13.5, 8.0 Hz, 1H), 1.99 (dd, J=13.5, 7.5 Hz, 1H), 1.92 (dt, J=12.9, 4.4 Hz, 1H), 1.76 (d, J=6.7 Hz, 3H), 1.58 (d, J=12.9 Hz, 1H), 1.42 (s+obscured m, 11H); LC/MS (10-99%) m/z 407.4 [M+H]⁺, retention time 2.70 min.

(S,S)-12c (3.0 g, 6.8 mmol), ammonium formate (8.5 g, 135.4 mmol, 20 eq), and 800 mg 10% Pd/C (wet, 50% by weight) were brought up in MeOH (30 mL) in a 100-mL flask fixed with a N₂ balloon. The mixture was stirred at room temperature for 28 h. The reaction mixture filtered through packed Celite and concentrated in vacuo to ˜10 mL. The concentrate was diluted with 50% saturated NaHCO₃ (200 mL), and the product extracted into EtOAc (3×100 mL). The combined extracts were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo to obtain (S)-12d as a colorless oil (2.0 g, 98% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.34 (m, 1H), 7.02-7.21 (m, 3H), 4.23 (t, J=7.7 Hz, 1H), 3.99 (m, 2H), 2.90 (br s, 2H), 2.57 (dd, J=12.7, 7.3 Hz, 1H), 2.00 (bs, 2H), 1.92 (dt, J=12.9, 4.5 Hz 1H), 1.42 (s+obscured m, 13H); LC/MS (10-99%) m/z 303.2 [M+H]⁺, 286.2 [m/z−NH₃]⁺, retention time 2.31 min.

(S)-12d (300 mg, 0.99 mmol) was dissolved in 1.5 mL anhydrous CH₃CN and cooled to 0° C., followed by ethyl chloroformate (118 mg, 1.09 mmol, 1.1 eq) and triethylamine (200 μL). White precipitate formed upon addition of the triethylamine. The reaction was allowed to warm to room temperature and then stirred for 1 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with 50% saturated NaHCO₃ (20 mL), water (20 mL), and brine (20 mL). The solution was dried over Na₂SO₄, filtered, and dried in vacuo to obtain product (S)-12e as a light yellow oil (>90% pure). LC/MS (10-99%) m/z 375.2 [M+H]⁺, retention time 3.43 min.

The crude (S)-12e was dissolved 5 mL CH₂Cl₂ and cooled to 0° C., followed by the addition of 5 mL TFA. The reaction mixture was stirred at 0° C. for 1 h, diluted with CH₃CN (20 mL), and dried in vacuo to obtain the (S)-12f TFA salt. The oil was dissolved in CH₂Cl₂ (30 mL), washed with 0.1 N NaOH (2×10 mL), brine (10 mL), dried over Na₂SO₄, filtered, and dried in vacuo to obtain the product (S)-12f as a light yellow oil (269 mg, 98% yield over 2 steps). LC/MS (10-99%) m/z 275.2 [M+H]⁺, retention time 1.42 min.

(S)-12f (269 mg, 0.98 mmol) was dissolved in cold DCE (1.5 mL) and treated with (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (119 mg, 0.98 mmol, 1.0 eq), followed by portion-wise addition of NaBH(OAc)₃ (300 mg, 1.4 mmol, 1.4 eq). The reaction was allowed to stir at room temperature for 1 h and was then quenched with MeOH (1 mL) and allowed to stir for another 30 min (until gas evolution stopped). The crude reaction mixture was purified by HPLC (10-99 CH₃CN gradient, 0.05% TFA) to provide the desired product (S)-12 g as the TFA salt. LC/MS (10-99%) m/z 381.2 [M+H]⁺, retention time 2.28 min.

The combined HPLC fractions (˜10 mL) were treated with 10% Pd/C (50 mg, wet, 50% by weight) under H₂ atmosphere with to cleanly provide (S)-12 g after 2 h of rapid stirring at room temperature. The solution was filtered through a 0.2 micron nylon filter and concentrated to provide 114 mg of compound no. 274 TFA salt (23% over 2 steps). LC/MS (10-99%) m/z 383.2 [M+H]⁺, retention time 2.28 min; ¹H-NMR (HCl salt, 400 MHz, DMSO-d₆) δ 10.39 (br s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.25 (m, 4H), 5.11 (m, 1H), 4.06 (q, J=7.0 Hz, 2H), 3.45 (m, 2H), 3.09 (m, 4H), 2.64 (m, 2H), 2.33 (br s, 2H), 2.15 (m, 2H), 1.84 (m, 1H), 1.67 (m, 3H), 1.48 (m, 2H), 1.34 (m, 3H), 1.20 (t, J=7.1 Hz, 3H), 1.14 (m, 1H), 0.88 (m, 1H).

Spiroindane (R)-compound no. 274 was produced utilizing an analogous synthetic route with the substitution of (R)-1-phenylethanamine for (S)-1-phenylethanamine in the synthesis of intermediate imine 12b (step 1).

Example 13

To a flask containing (S,S)-13a (See Example 12, 1.5 g, 3.39 mmol) and K₂CO₃ (1.87 g, 13.54 mmol, 4 eq) was added 2 mL anhydrous DMF followed by 8 mL anhydrous THF. The mixture was treated with MeI (2.40 g, 16.93 mmol, 5 eq) and heated to 45° C. for 6 h, followed by stirring at room temperature for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with 20% saturated NH₄Cl (50 mL), 50% saturated NaHCO₃ (50 mL), brine (50 mL). The solution was dried over Na₂SO₄, filtered, and dried in vacuo to yield a reddish oil. The oil was dissolved in diethyl ether and filtered to remove insoluble material, followed by treatment with 1 eq of ethereal HCl. The resulting solution was dried down in vacuo to yield crude (S)-13b as a light orange solid. LC/MS (10-99%) m/z 421.0 [M+H]⁺, retention time 2.77 min.

Crude (S)-13b was dissolved in CH₂Cl₂ (50 mL) and cooled to −10° C., followed by the addition of 10 mL TFA. The reaction mixture was stirred at −10° C. for 1 h, diluted with CH₃CN (20 mL), and dried in vacuo to obtain the (S)-13c TFA salt. The oil was dissolved in CH₂Cl₂ (30 mL), washed with 50% saturated NaHCO₃ (2×10 mL), brine (10 mL), dried over Na₂SO₄, filtered, and dried in vacuo to obtain the product (S)-13c as a colorless oil (673 mg, 67% yield over 2 steps). ¹H NMR (400 MHz, DMSO-d₆) δ 7.46 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.16-7.25 (m, 5H), 4.66 (t, J=8.0 Hz, 1H), 3.79 (q, J=6.7 Hz, 1H), 2.99 (app t, J=12.0 Hz, 2H), 2.79 (dt, J=12.4, 2.5 Hz, 1H), 2.69 (dt, J=12.7, 2.3 Hz, 1H), 2.07 (q, J=8.0 Hz, 1H), 1.97 (dt, J=13.3, 4.2 Hz, 1H), 1.85 (s, 3H), 1.73 (m, 1H), 1.52 (dt, J=12.7, 4.2 Hz, 1H), 1.42 (d, J=6.6 Hz, 3H), 1.36 (app t, J=12.9 Hz, 3H); LC/MS (10-99%) m/z 321.2 [M+H]⁺, retention time 1.60 min.

(S)-13c (650 mg, 2.03 mmol) and (1S,2S,4S)-bicyclo[2.2.1]hept-5-ene-2-carbaldehyde (262 mg, 2.15 mmol) were dissolved in DCE (13 mL) and the mixture cooled to −30° C., followed by portion-wise addition of NaBH(OAc)₃ (646 mg, 3.05 mmol). The reaction was stirred at −30° C. for 2 h and was the allowed to come to room temperature and stirred for 16 h. The reaction was quenched with MeOH (5 mL) and diluted with EtOAc (200 mL). The crude reaction was washed with 50% saturated NaHCO₃ (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over Na₂SO₄, filtered and dried in vacuo to yield the product (S)-13d as a colorless oil (802 mg, 93% yield).

(S)-13d (800 mg, 6.8 mmol), ammonium formate (2.36 g, 37.5 mmol), and 800 mg 10% Pd/C (wet, 50% by weight) were brought up in MeOH (8 mL) in a 25-mL flask fixed with a N₂ balloon. The mixture was stirred at room temperature for 24 h. 1.18 g of ammonium formate were added and the mixture stirred for an additional 24 h. The reaction mixture was filtered through packed Celite, diluted with 50% saturated NaHCO₃ (200 mL), and the product (S)-13e extracted into EtOAc (5×75 mL). The combined extracts were washed with brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo to obtain (S)-13e as a colorless oil (493 mg, 81% yield). LC/MS (10-99%) m/z 325.4 [M+H]⁺, retention time 1.52 min.

(S)-13e (123 mg, 0.38 mmol) was dissolved in 1.5 mL anhydrous CH₃CN and cooled to 0° C., followed by the additional of acetyl chloride (33 mg, 0.42 mmol) and triethylamine (200 μl). White precipitate formed upon addition of the triethylamine. The reaction was allowed to warm to room temperature and then stirred for 1 h. The crude reaction mixture was purified by HPLC (10-99 CH₃CN gradient, 0.05% TFA) to provide the desired compound no. 190 as the TFA salt (65 mg, 47% yield). LC/MS (10-99%) m/z 367.2 [M+H]⁺, retention time 1.99 min.

Spiroindane (R) form of compound no. 190 was produced utilizing an analogous synthetic route with the substitution of (R)-1-phenylethanamine for (S)-1-phenylethanamine in the synthesis of intermediate 13a (See Example 12).

Example 14

Intermediate 14a (49 mg; 0.2 mmol) and 4-formyl-4-methylpiperidine-1-carboxylate (40 mg; 0.2 mmol) were dissolved in DCE (2 mL) and NaBH(OAc)₃ (85 mg; 0.4 mmol) was added. The reaction was stirred at room temperature for 20 hours. The reaction was diluted with DCM (10 mL) and 1N HCl (20 mL), the layers were separated, and the organic layer was discarded. The aqueous layer was washed with DCM (10 mL) and then was basified with NaOH. The aqueous layer was then washed with EtOAc (3×20 mL) and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under high vacuum. The crude product compound no. 314 was purified using reversed-phase chromatography (2-99% CH₃CN/H₂O gradient with 0.05% TFA). LC/MS m/z [M+H]⁺428.2, retention time 1.85 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min); ¹H-NMR (400 MHz, DMSO-d₆) δ 8.50 (br s, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.27 (m, 4H), 5.35 (m, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.69 (m, 2H), 3.53 (m, 2H), 3.31 (m, 2H), 3.18 (m, 5H), 2.69 (m, 1H), 2.07 (m, 1H), 1.89 (s, 3H), 1.66 (m, 3H), 1.50 (m, 4H), 1.19 (overlapping q and s, 6H).

Example 15

The mixture of N-Boc protected spiroindanone 15a (20 g, 66.4 mmol) and MeOH/HCl (2.5 mol/L, 100 mL) were stirred overnight. After evaporation the residue was washed by petroleum ether to gave the corresponding amine hydrochloride 15b (15.4 g, 97.6%).

To a solution of compound 15b (5.0 g, 24.84 mmol) and Et₃N (7.54 g, 74.53 mol) in CH₂Cl₂ (50 mL) was added drop-wise Cbz-Cl (4.66 g, 27.33 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The precipitate was filtered, washed with Et₂O and dried to furnish compound 15c (6.1 g, yield 99%).

A solution of compound 15c (3 g, 10.3 mmol) in EtOH (30 mL) containing NH₂OH.HCl (1.43 g, 20.6 mmol) and NaOAc (1.52 g, 18.53 mmol) was heated under reflux for 1.5 h. The solvent was removed by evaporation and the residue was partitioned between CH₂Cl₂ and water. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to give compound 15d (3.14 g, yield 99%), which could be used directly in the next step.

2,4,6-trichloro-[1,3,5]-triazine (1.32 g, 7.16 mmol) was added to DMF (9.6 mL) maintained at 25° C. The reaction was monitored by TLC until TCT was consumed. Then compound 15d (1.6 g, 4.77 mmol) in DMF (17 mL) was added. After the addition, the mixture was stirred at room temperature overnight. Water was added. The mixture was extracted with EtOAc. The combined organic layers were washed with sat. Na₂CO₃, followed by 1N HCl and brine, dried over Na₂SO₄ and concentrated. The residue was purified by prep HPLC to obtain compound 15e (260 mg, yield 16%).

The mixture of compound 15e (1.2 g, 3.4 mmol) and Pd/C (200 mg) in MeOH (20 mL) was hydrogenated under atmosphere pressure at room temperature for 3 h. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC twice to give 15f (110 mg, 11%) as a TFA salt. ¹H NMR (CDCl₃) δ 7.65 (d, J=7.5 Hz, 1H), 7.29-7.45 (m, 3H), 3.45 (d, J=12.3 Hz, 2H), 3.20 (t, J=12.3 Hz, 2H), 2.96 (s, 2H), 2.10-2.21 (m, 2H), 1.70 (d, J=14.1 Hz, 2H). MS (ESI) m/z 217.06 [M+H]⁺.

Amine 15f (22 mg, 0.1 mmol) and ethyl 4-formylpiperidine-1-carboxylate (28 mg, 0.15 mmol) were dissolved in DCE (1 mL) and NaBH(OAc)₃ (42 mg; 0.2 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction was diluted methanol (0.5 mL), filtered, and compound no. 34 was purified using reversed-phase chromatography (10-99% CH₃CN/H₂O gradient with 0.05% TFA). LC/MS m/z 386.2 [M+H]⁺, retention time 2.05 min (10-99% CH₃CN—H₂O gradient with 0.03% TFA, 5 min); ¹H NMR (free base, 400 MHz, DMSO-d₆) δ 7.71 (d, J=3.9 Hz, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.47-7.41 (m, 1H), 4.05-3.96 (m, 4H), 2.86-2.67 (m, 4H), 2.56 (d, J=9.7 Hz, 2H), 2.18 (s, 2H), 2.01 (d, J=7.7 Hz, 4H), 1.73 (d, J=11.1 Hz, 4H), 1.45 (d, J=8.7 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.03-0.96 (m, 2H).

Example 16

A stirred mixture of sodium hydride (60%, 31 g, 0.79 mol) in dry xylene (500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min. 1,3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added via an addition funnel and stirred at reflux for 1.5 hrs. Dimethyl sulfate (104 g, 0.83 mol) was added drop-wise, whereupon the resulting homogeneous solution was refluxed for an additional 2 hrs. After cooling to room temperature, the reaction mixture was washed with water, dried over Na₂SO₄, and concentrated under reduced pressure to afford 1-methyl-1,3-dihydro-indol-2-one 16b (74 g, 67.3%). ¹H NMR (300 MHz, CDCl₃) δ 7.23-7.31 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 3.52 (s, 2H), 3.21 (s, 3H).

A suspension of NaH (60%, 70 g, 0.48 mol) in THF (300 mL) was stirred for 10 min at 0° C. Then a solution of 1-methyl-1,3-dihydro-indol-2-one 16b (70 g, 2.88 mol) in THF (200 mL) was added at 0° C., and the mixture was stirred for 1 h at room temperature. Benzyl-bis-(2-chloro-ethyl)-amine (129 g, 0.48 mol) was added in portions at 0° C. The mixture was stirred overnight at room temperature, and then was poured into ice-water, extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column on silica gel (P.E./E.A. 2:1) to give compound 16c (24 g, 16.3%). ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.42 (m, 7H), 7.02-7.07 (m, 1H), 6.83 (d, J=7.5, 1H), 3.68 (s, 2H), 3.19 (s, 3H), 2.74-2.99 (m, 2H), 2.66-2.72 (m, 2H), 1.93-2.01 (m, 2H), 1.79-1.85 (m, 2H).

To a solution of compound 16c (12 g, 39.2 mmol) in MeOH (100 mL) was added Pd(OH)₂/C (1.5 g, 20%) under N₂. The suspension was hydrogenated under H₂ (50 psi) at room temperature for 4.5 hrs. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the deprotected spiroindolone product 16d (8 g, 94.5%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.46 (d, J=7.2, 1H), 7.23-7.27 (m, 1H), 6.96-7.03 (m, 2H), 3.04-3.14 (m, 5H), 2.83-2.89 (m, 2H), 1.61-1.67 (m, 2H), 1.45-1.51 (m, 2H). MS (ESI) m/z 217.1 [M+H]⁺

1.0 eq of deprotected spiroindolone 16d (22 mg, 0.10 mmol) was dissolved in anhydrous 1,2-dichloroethane:1,2-dimethoxyethane (1.0 mL, 1:1 v/v) and treated with 1.5 N-Carbethoxy-4-tropinone (30 mg, 0.15 mmol), followed by titanium tetraisopropoxide (88 μL, 85 mg, 0.30 mmol). The vial was flushed with nitrogen and stirred at room temperature ˜70 h. The reaction was then diluted with methanol (1.0 mL), cooled in an ice-H₂O bath and treated with sodium borohydride (8 mg, 0.20 mmol). After warming to room temperature and stirring for 90 min, the reaction was further diluted with methanol (2.0 mL), quenched with 1.0 N NaOH (500 μL) and stirred vigorously at room temperature for 10 min. The suspension obtained was centrifuged (3K rpm, 10 min) and the supernatant concentrated under reduced pressure. The residue obtained was dissolved in MeOH:acetonitrile (1250 μL, 1:1 v/v), filtered, and purified by reverse-phase HPLC (2-40% CH₃CN/0.1% TFA gradient over 10 min) to yield product compound no. 149. LC/MS (10-99%) m/z [M+H]⁺398.2, retention time 1.93 min.

Example 17

Compound no. 364 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CDCl₃) δ 1.27 (t, J=6.3 Hz, 3H), 1.56 (d, J=11.5 Hz, 2H), 1.67 (q, J=7.0 Hz, 4H), 1.82 (m, 2H), 1.97 (m, 6H), 2.29 (t, J=11.5 Hz, 2H), 2.82 (m, 1H), 2.89 (dd, J=13.7, 6.5 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 4.35 (d, J=24.4 Hz, 2H), 7.17 (m, 4H).

Example 18

Compound no. 413 was synthesized using known methods and those described above.

¹H NMR (free base, 400 MHz, DMSO-d6) δ 7.20-7.10 (m, 4H), 4.02 (q, J=7.1 Hz, 2H), 3.99-3.96 (m, 2H), 2.84 (t, J=7.3 Hz, 2H), 2.81-2.77 (m, 4H), 2.16 (d, J=4.9 Hz, 2H), 2.06 (t, J=12.2 Hz, 2H), 1.94 (t, J=7.3 Hz, 2H), 1.80 (t, J=11.3 Hz, 2H), 1.74-1.70 (m, 3H), 1.43 (d, J=12.5 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.02-0.93 (m, 2H).

Example 19

Compound no. 375 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 6.99 (dt, J=12.8, 4.5 Hz, 1H), 6.91 (dd, J=8.0, 2.7 Hz, 1H), 6.82 (dd, J=8.7, 4.1 Hz, 1H), 6.25 (q, J=2.9 Hz, 1H), 6.07 (q, J=2.7 Hz, 1H), 4.50 (s, 2H), 3.51 (t, J=13.2 Hz, 2H), 3.04-2.96 (m, 3H), 2.91-2.84 (m, 2H), 2.74-2.68 (m, 1H), 2.40-2.30 (m, 2H), 2.03-1.97 (m, 2H), 1.88 (d, J=14.2 Hz, 2H), 1.32 (dd, J=33.8, 7.1 Hz, 2H), 0.69 (d, J=11.4 Hz, 1H).

Example 20

Compound no. 181 was synthesized using known methods and those described above.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.03 (br s, 1H), 7.21 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.52 (s, 2H), 3.41 (m, 2H), 3.25 (m, 1H), 3.01 (m, 2H), 2.63 (m, 2H), 2.44 (m, 1H), 2.27 (m, 1H), 1.86 (m, 4H), 1.51 (m, 3H), 1.39 (m, 2H), 1.24 (m, 1H).

Example 21

Compound no. 23 was synthesized using known methods and those described above.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.27 (br s, 1H), 8.53 (br s, 1H), 6.93 (d, J=7.9 Hz, 1H), 6.88 (s, 1H), 6.72 (d, J=7.9 Hz, 1H), 3.48 (s, 2H), 3.40 (m, 3H), 3.04 (m, 2H), 2.64 (m, 1H), 2.57 (br s, 1H), 2.38 (m, 1H), 2.26 (m, 1H), 2.24 (s, 3H), 1.94 (m, 2H), 1.78 (m, 2H), 1.55 (m, 3H), 1.39 (m, 3H).

Example 22

Compound no. 367 was synthesized using known methods and those described above.

¹H-NMR (300 MHz, CDCl₃): δ 7.08 (m, 1H), 6.95 (m, 2H), 4.28 (br s, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.62 (m, 2H), 3.00 (m, 2H), 2.91 (m, 2H), 2.49 (m, 3H), 1.95-2.02 (m, 6H), 1.69 (m, 2H), 1.48 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).

Example 23

Compound no. 370 was synthesized using known methods and those described above.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.65 (br s, 1H), 8.05 (dd, J=8.9, 4.9 Hz, 1H), 7.06 (td, J=9.0, 2.7 Hz, 1H), 6.92 (dd, J=8.3, 2.7 Hz, 1H), 4.27 (br s, 2H), 4.08 (m, 4H), 3.74 (m, 1H), 3.55 (br s, 2H), 3.06 (m, 2H), 2.30 (m, 2H), 2.20 (s, 3H), 2.07 (m, 2H), 1.86 (m, 6H), 1.67 (m, 2H), 1.22 (t, J=7.1 Hz, 3H).

Example 24

Compound no. 422 was synthesized using known methods and those described above.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.61 (br s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.96 (s, 1H), 4.06 (s, 2H), 3.96 (m, 3H), 3.59 (s, 3H), 3.51 (m, 2H), 3.11 (m, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.83 (br s, 2H), 2.47 (m, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 2.11 (m, 1H), 1.88 (m, 2H), 1.77 (m, 2H), 1.13 (m, 2H).

Example 25

Compound no. 92 was synthesized using known methods and those described above.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.97 (br s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.95 (s, 1H), 4.13 (m, 2H), 4.06 (m, 4H), 3.45 (m, 3H), 3.12 (m, 2H), 2.83 (br s, 2H), 2.43 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H), 2.17 (m, 2H), 1.82 (m, 2H), 1.64 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

Example 26

Compound no. 412 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.05 (q, J=4.6 Hz, 1H), 7.06 (dt, J=12.9, 4.5 Hz, 1H), 6.94 (dd, J=8.3, 2.6 Hz, 1H), 4.13-4.09 (m, 4H), 4.05 (q, J=7.1 Hz, 2H), 3.50-3.39 (m, 3H), 3.13 (q, J=11.4 Hz, 2H), 2.83 (bs, 2H), 2.46 (t, J=13.5 Hz, 2H), 2.20 (s, 3H), 2.16 (d, J=11.6 Hz, 2H), 1.88 (d, J=13.8 Hz, 2H), 1.67-1.59 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

Example 27

Compound no. 361 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 1.22 (t, J=7.2 Hz, 3H), 1.66 (d, J=6.5 Hz, 2H), 1.87 (m, 6H), 2.05 (s, 2H), 2.21 (t, J=12.3 Hz, 2H), 2.87 (s, 6H), 3.05 (m, 2H), 3.52 (d, J=11.6 Hz, 2H), 3.73 (m, 1H), 3.84 (s, 2H), 4.08 (q, J=7.1 Hz, 2H), 4.26 (s, 2H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (m, 2H), 10.38 (br s, 1H).

Example 28

Compound no. 39 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.25 (t, J=7.1 Hz, 3H), 1.66 (qd, J=12.3, 4.5 Hz, 2H), 1.98 (s, 2H), 2.10 (d, J=11.8 Hz, 2H), 2.28 (td, J=14.2, 3.7 Hz, 2H), 2.81 (t, J=15.9 Hz, 2H), 2.92 (s, 6H), 3.08 (q, J=11.3 Hz, 2H), 3.38 (dd, J=13.4, 10.5 Hz, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 4.26 (d, J=12.1 Hz, 2H), 6.97 (m, 3H).

Example 29

Compound no. 91 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 0.96 (t, J=7.4 Hz, 3H), 1.66 (m, 4H), 1.98 (s, 2H), 2.10 (d, J=11.3 Hz, 2H), 2.28 (dt, J=19.9, 7.2 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.2 Hz, 2H), 3.38 (t, J=12.2 Hz, 1H), 3.52 (d, J=11.9 Hz, 2H), 3.87 (s, 2H), 4.02 (t, J=6.6 Hz, 2H), 4.27 (d, J=12.8 Hz, 2H), 6.97 (m, 3H).

Example 30

Compound no. 54 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.24 (d, J=6.2 Hz, 6H), 1.65 (dq, J=12.3, 4.5 Hz, 2H), 1.99 (s, 2H), 2.09 (d, J=11.9 Hz, 2H), 2.25 (td, J=14.2, 3.7 Hz, 2H), 2.81 (t, J=11.4 Hz, 2H), 2.93 (s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.39 (m, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 4.26 (d, J=12.8 Hz, 2H), 4.86 (heptet, J=6.2 Hz, 1H), 6.98 (m, 3H).

Example 31

Compound no. 208 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.67 (dq, J=12.2, 4.2 Hz, 2H), 2.15 (m, 4H), 2.27 (t, J=14.2 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.39 (t, J=12.0 Hz, 1H), 3.52 (d, J=12.0 Hz, 2H), 3.82 (m, 6H), 3.87 (s, 2H), 4.25 (d, J=11.2 Hz, 2H), 5.19 (s, 1H), 6.96 (m, 3H).

Example 32

Compound no. 120 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.67 (dq, J=12.2, 4.2 Hz, 2H), 2.15 (m, 4H), 2.27 (t, J=14.2 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.39 (t, J=12.0 Hz, 1H), 3.52 (d, J=12.0 Hz, 2H), 3.82 (m, 6H), 3.87 (s, 2H), 4.25 (d, J=11.2 Hz, 2H), 5.19 (s, 1H), 6.96 (m, 3H).

Example 33

Compound no. 48 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.69 (dq, J=12.3, 4.1 Hz, 2H), 1.99 (s, 2H), 2.12 (d, J=11.5 Hz, 2H), 2.28 (t, J=14.1 Hz, 2H), 2.87 (brs, 2H), 2.92 (s, 6H), 3.09 (q, J=11.3 Hz, 2H), 3.40 (t, J=11.9 Hz, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.87 (s, 2H), 4.27 (m, 3H), 4.34 (m, 1H), 4.56 (t, J=3.9 Hz, 1H), 4.68 (t, J=3.9 Hz, 1H), 6.97 (m, 3H).

Example 34

Compound no. 352 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.68 (qd, J=12.3, 4.5 Hz, 2H), 1.85 (t, J=2.3 Hz, 3H), 1.98 (s, 2H), 2.12 (d, J=12.1 Hz, 2H), 2.30 (td, J=14.1, 3.7 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.0 Hz, 2H), 3.39 (t, J=12.1 Hz, 1H), 3.51 (d, J=11.8 Hz, 2H), 3.87 (s, 2H), 4.25 (br s, 2H), 4.65 (d, J=2.1 Hz, 2H), 6.98 (m, 3H).

Example 35

Compound no. 127 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.68 (qd, J=12.3, 4.4 Hz, 2H), 1.99 (s, 2H), 2.11 (d, J=12.3 Hz, 2H), 2.27 (m, 2H), 2.55 (td, J=6.6, 2.7 Hz, 2H), 2.85 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=11.1 Hz, 2H), 3.39 (t, J=11.9 Hz, 1H), 3.51 (d, J=12.4 Hz, 2H), 3.87 (s, 2H), 4.15 (t, J=6.6 Hz, 2H), 4.26 (d, J=13.2 Hz, 2H), 6.97 (m, 3H).

Example 36

Compound no. 264 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.67 (qd, J=12.3, 4.3 Hz, 2H), 1.99 (s, 2H), 2.11 (d, J=10.6 Hz, 2H), 2.29 (t, J=14.1 Hz, 2H), 2.87 (br s, 2H), 2.92 (s, 6H), 3.08 (q, J=10.9 Hz, 2H), 3.34 (s, 3H), 3.40 (t, J=6.6 Hz, 1H), 3.52 (d, J=6.3 Hz, 2H), 3.57 (t, J=4.6 Hz, 2H), 3.86 (s, 2H), 4.18 (dd, J=5.1, 4.0 Hz, 2H), 4.26 (d, J=12.7 Hz, 2H), 6.96 (m, 3H).

Example 37

Compound no. 172 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.71 (qd, J=12.3, 4.4 Hz, 2H), 1.99 (s, 2H), 2.14 (d, J=14.4 Hz, 2H), 2.22 (s, 3H), 2.35 (td, J=14.2, 3.4 Hz, 2H), 2.89 (br s, 2H), 3.10 (q, J=10.6 Hz, 2H), 3.41 (t, J=11.4 Hz, 1H), 3.53 (d, J=12.6 Hz, 2H), 4.06 (s, 2H), 4.28 (m, 2H), 4.35 (t, J=4.0 Hz, 1H), 4.57 (t, J=4.0 Hz, 1H), 4.69 (t, J=4.0 Hz, 1H), 7.01 (m, 2H), 8.14 (dd, J=8.8, 4.9 Hz, 1H).

Example 38

Compound no. 102 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.71 (qd, J=12.3, 4.4 Hz, 2H), 1.85 (t, J=2.4 Hz, 3H), 1.99 (s, 2H), 2.13 (d, J=12.2 Hz, 2H), 2.22 (s, 3H), 2.35 (td, J=14.1, 3.6 Hz, 2H), 2.88 (br s, 2H), 3.09 (q, J=11.2 Hz, 2H), 3.40 (t, J=12.0 Hz, 1H), 3.53 (d, J=12.7 Hz, 2H), 4.06 (s, 2H), 4.26 (br s, 2H), 4.66 (d, J=2.2 Hz, 2H), 6.99 (td, J=9.0, 2.7 Hz, 1H), 7.05 (dd, J=8.6, 2.6 Hz, 1H), 8.14 (dd, 8.7, 4.8, 1H).

Example 39

Compound no. 62 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.70 (qd, J=12.2, 4.3 Hz, 2H), 1.99 (s, 2H), 2.13 (d, J=11.1 Hz, 2H), 2.22 (s, 3H), 2.27 (t, J=2.6 Hz, 1H), 2.36 (td, J=14.0, 3.5 Hz, 2H), 2.55 (td, J=6.6, 2.7 Hz, 2H), 2.87 (br s, 2H), 3.09 (q, J=10.4 Hz, 2H), 3.40 (t, J=12.1 Hz, 1H), 3.53 (d, J=12.3 Hz, 2H), 4.06 (s, 2H), 4.16 (t, J=6.6 Hz, 2H), 4.28 (d, J=12.6 Hz, 2H), 6.99 (td, J=9.0, 2.6 Hz, 1H), 7.05 (dd, J=8.6, 2.6 Hz, 1H), 8.13 (dd, J=8.8, 4.9 Hz, 1H).

Example 40

Compound no. 32 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.72 (d, J=7.3 Hz, 2H), 1.91 (d, J=2.5 Hz, 2H), 1.99 (s, 2H), 2.10 (m, 2H), 2.31 (td, J=14.0, 3.7 Hz, 2H), 2.91 (s, 6H), 2.96 (m, 2H), 3.36 (m, 2H), 3.57 (d, J=12.4 Hz, 2H), 3.63 (br s, 1H), 3.84 (s, 2H), 4.29 (t, J=4.0 Hz, 1H), 4.37 (m, 3H), 4.58 (t, J=3.9 Hz, 1H), 4.70 (t, J=3.9 Hz, 1H), 6.96 (m, 3H).

Example 41

Compound no. 200 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.72 (d, J=7.2 Hz, 2H), 1.85 (t, J=2.4 Hz, 3H), 1.98 (m, 4H), 2.11 (m, 2H), 2.30 (td, J=14.0, 3.6 Hz, 2H), 2.91 (s, 6H), 2.96 (br s, 2H), 3.08-3.72 (m, 5H), 3.84 (s, 2H), 4.37 (s, 2H), 4.67 (d, J=16.6 Hz, 2H), 6.96 (m, 3H).

Example 42

Compound no. 229 was synthesized using known methods and those described above.

¹H NMR (400 MHz, CD₃CN) δ 1.66 (br s, 2H), 1.84 (br s, 2H), 1.92 (br s, 2H), 1.98 (br s, 2H), 2.23 (m, 3H), 2.50 (dd, J=6.4, 2.5 Hz, 2H), 2.84 (s, 6H), 2.93 (m, 2H), 3.08 (m, 2H), 3.50 (d, J=10.9 Hz, 2H), 3.65 (br s, 1H), 3.77 (s, 2H), 4.11 (s, 2H), 4.30 (s, 2H), 6.90 (m, 3H).

Example 43

Compound no. 165 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.74 (q, J=1.3 Hz, 1H), 7.65 (q, J=2.6 Hz, 1H), 7.60 (dd, J=8.4, 1.7 Hz, 1H), 7.49 (dd, J=5.0, 1.2 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 4.16-4.10 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.56-3.49 (m, 3H), 3.19 (q, J=11.3 Hz, 2H), 2.85 (br s, 2H), 2.28-2.23 (m, 5H), 2.10 (d, J=12.9 Hz, 2H), 1.96 (d, J=13.9 Hz, 2H), 1.66-1.57 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

Example 44

Compound no. 406 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.39 (d, J=10.3 Hz, 1H), 5.78-5.69 (m, 1H), 4.15-4.10 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 3.58-3.49 (m, 3H), 3.16 (q, J=10.8 Hz, 2H), 2.84 (br s, 2H), 2.21 (s, 3H), 2.16-2.07 (m, 4H), 1.93 (d, J=13.9 Hz, 2H), 1.87 (d, J=7.2 Hz, 3H), 1.63-1.55 (m, 2H), 1.20 (t, J=7.1 Hz, 3H

Example 45

Compound no. 158 was synthesized using known methods and those described above.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.40 (br s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.27 (m, 4H), 5.34 (m, 1H), 3.40 (m, 3H), 3.13 (m, 1H), 2.97 (m, 2H), 2.65 (m, 1H), 2.57 (br s, 1H), 2.30 (m, 2H), 1.97 (m, 2H), 1.88 (s, 3H), 1.65 (m, 4H), 1.46 (m, 5H).

Example 46

Compound no. 182 was synthesized using known methods and those described above.

¹H-NMR (400 MHz, DMSO-d₆) δ 10.43 (br s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.28 (m, 4H), 5.34 (m, 1H), 3.96 (br m, 2H), 3.59 (s, 3H), 3.50 (m, 2H), 3.07 (m, 4H), 2.72 (m, 4H), 2.28 (m, 1H), 2.08 (m, 1H), 1.88 (s, 3H), 1.85 (m, 2H), 1.66 (m, 3H), 1.12 (m, 2H).

Example 47

Compound no. 358 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.30 (d, J=8.1 Hz, 1H), 7.34-7.31 (m, 1H), 7.27 (dt, J=10.1, 3.7 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 5.33 (q, J=7.8 Hz, 1H), 4.26 (m, 2H), 4.08 (q, J=7.0 Hz, 2H), 3.77-3.70 (m, 1H), 3.52 (t, J=13.0 Hz, 2H), 3.06 (q, J=11.5 Hz, 1H), 2.97 (q, J=11.8 Hz, 1H), 2.61 (dd, J=13.2, 8.0 Hz, 1H), 2.54-2.47 (m, 1H), 2.15-2.04 (m, 3H), 1.91-1.81 (m, 7H), 1.71-1.66 (m, 5H), 1.22 (t, J=7.1 Hz, 3H).

Example 48

Compound no. 191 was synthesized using known methods and those described above.

¹H NMR (free base, 400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.18 (dt, J=10.6, 3.8 Hz, 1H), 6.94 (dt, J=10.4, 3.8 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 4.03 (q, J=7.1 Hz, 4H), 2.94-2.88 (m, 2H), 2.79 (s, 2H), 2.72-2.66 (m, 2H), 2.58-2.51 (m, 1H), 1.82-1.75 (m, 4H), 1.64-1.59 (m, 2H), 1.43-1.33 (m, 2H), 1.18 (t, J=7.1 Hz, 3H).

Example 49

Compound no. 199 was synthesized using known methods and those described above.

¹H NMR ((free base, 400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.17 (dt, J=10.5, 3.8 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 4.18 (m, 2H), 4.05 (q, J=6.5 Hz, 2H), 2.94-2.84 (m, 3H), 2.63 (t, J=8.1 Hz, 2H), 1.97-1.83 (m, 3H), 1.78-1.70 (m, 5H), 1.62-1.58 (m, 4H), 1.19 (t, J=7.1 Hz, 3H).

Example 50

Compound no. 318 was synthesized using known methods and those described above.

Compound was prepared using reductive amination conditions described above. ¹H NMR ((free base, 400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 7.46 (d, J=7.4 Hz, 1H), 7.18 (dt, J=10.6, 3.8 Hz, 1H), 6.94 (dt, J=10.4, 3.8 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.97 (m, 2H), 2.82-2.77 (m, 4H), 2.56-2.52 (m, 1H), 2.27 (d, J=6.8 Hz, 2H), 1.84-1.72 (m, 5H), 1.63-1.59 (m, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.04-0.94 (m, 2H).

Example 51

Compound no. 104 was synthesized using known methods and those described above.

¹H NMR (free base, 400 MHz, DMSO-d6) δ 7.74-7.68 (m, 2H), 7.61 (d, J=7.6 Hz, 1H), 7.46-7.42 (m, 1H), 6.17-6.15 (m, 1H), 5.97-5.95 (m, 1H), 2.95-2.76 (m, 4H), 2.55 (s, 2H), 2.36-2.28 (m, 1H), 2.09-1.99 (m, 6H), 1.87-1.81 (m, 1H), 1.45 (d, J=3.9 Hz, 2H), 1.34-1.20 (m, 2H), 0.55-0.51 (m, 1H)

Example 52

Compound no. 186 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (br s, 1H), 7.07-6.95 (m, 2H), 6.85-6.82 (m, 1H), (tt, J=28.8, 18.1 Hz, 1H), 4.51 (s, 2H), 4.40-4.31 (m, 4H), 3.74 (q, J=5.5 Hz, 1H), 3.59-3.40 (m, 4H), 2.98 (q, J=10.8 Hz, 2H), 2.07-1.93 (m, 8H), 1.68 (d, J=5.5 Hz, 4H).

Example 53

Compound no. 275 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.25 (br s, 1H), 7.32 (d, J=2.6 Hz, 1H), 7.16 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 4.11 (t, J=5.1 Hz, 2H), 3.38-3.34 (m, 2H), 3.25-3.13 (m, 3H), 2.31-2.23 (m, 2H), 2.08-2.04 (m, 4H), 1.85 (d, J=13.7 Hz, 4H), 1.63 (d, J=12.6 Hz, 1H), 1.49-1.39 (m, 2H), 1.34-1.29 (m, 2H), 1.21 (m, 1H)

Example 54

Compound no. 258 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 9.20 (bs, 1H), 7.30-7.15 (m, 2H), 7.07-6.87 (m, 2H), 3.65-3.35 (m, 5H), 2.66-2.64 (m, 1H), 2.40-2.30 (m, 3H), 2.07-1.98 (m, 1H), 1.92 (d, J=14.7 Hz, 1H), 1.79 (d, J=14.3 Hz, 1H), 1.68-1.51 (m, 3H), 1.47-1.38 (m, 3H), 1.27-1.20 (m, 1H).

Example 55

Compound no. 152 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (br s, 1H), 7.04-6.93 (m, 2H), 6.84-6.80 (m, 1H), 4.53 (s, 2H), 3.47 (d, J=12.1 Hz, 1H), 3.40-3.38 (m, 1H), 3.24-3.17 (m, 1H), 3.06 (q, J=11.3 Hz, 2H), 2.19-2.11 (m, 2H), 2.05 (d, J=10.2 Hz, 2H), 1.94 (d, J=14.1 Hz, 2H), 1.84 (d, J=12.9 Hz, 2H), 1.63 (d, J=12.5 Hz, 1H), 1.46-1.23 (m, 4H), 1.17-1.07 (m, 1H).

Example 56

Compound no. 288 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (br s, 1H), 7.05-6.92 (m, 2H), 6.85-6.80 (m, 1H), 6.34-6.31 (m, 1H), 4.50 (s, 2H), 4.33 (d, J=13.4 Hz, 2H), 3.83-3.74 (m, 1H), 3.67-3.51 (m, 3H), 2.95 (q, J=11.0 Hz, 2H), 2.07-1.85 (m, 8H), 1.74-1.58 (m, 4H), 1.08 (d, J=6.6 Hz, 6H).

Example 57

Compound no. 211 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (br s, 1H), 7.06-6.95 (m, 2H), 6.85-6.80 (m, 1H), 5.18 (s, 1H), 4.51 (s, 2H), 4.25 (s, 2H), 3.81-3.71 (m, 5H), 3.58 (d, J=12.1 Hz, 2H), 2.98-2.93 (m, 2H), 2.13-1.94 (m, 10H), 1.65 (d, J=7.4 Hz, 4H).

Example 58

Compound no. 156 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (br s, 1H), 7.06-6.95 (m, 2H), 6.86-6.80 (m, 1H), 4.51 (s, 2H), 4.26 (s, 2H), 3.57-3.44 (m, 6H), 2.97 (q, J=11.1 Hz, 2H), 2.08-2.02 (m, 4H), 1.94 (d, J=13.5 Hz, 4H), 1.70-1.65 (m, 4H).

Example 59

Compound no. 181 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (br s, 1H), 7.21 (dd, J=8.5, 2.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.52 (s, 2H), 3.47-3.21 (m, 3H), 3.10-2.94 (m, 2H), 2.66-2.40 (m, 3H), 2.27 (s, 1H), 1.96-1.83 (m, 4H), 1.56-1.53 (m, 3H), 1.42-1.33 (m, 3H).

Example 60

Compound no. 178 was synthesized using known methods and those described above.

¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (br s, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.18-7.16 (m, 1H), 6.84-6.81 (m, 1H), 4.14-3.99 (m, 2H), 3.46 (d, J=12.1 Hz, 4H), 3.36-3.31 (m, 2H), 3.20-3.11 (m, 3H), 2.28-2.20 (m, 2H), 2.07-2.00 (m, 4H), 1.88 (d, J=14.4 Hz, 2H), 1.75-1.64 (m, 2H).

Example 61 Physical Characteristics of Compounds of Formulae (I and II)

Additional compounds having the structures shown in Table 1 were synthesized using known methods and those described above.

TABLE 2 Physical Characteristics of Compounds in Table 1 Cmd LCMS LCMS No. Plus RT 2 327.3 2.8 3 309 1.88 4 379.2 1.99 5 306.2 2.32 6 476.2 2.34 7 309.4 1.93 8 353.3 2.16 9 426.2 1.94 10 519.4 1.92 11 412.2 1.98 12 397.5 2.48 13 328.2 2.05 14 460.5 2.13 15 369.2 2.19 16 508.5 2.2 17 458.4 2.35 18 286 2.13 19 378.2 1.94 20 336.4 2.23 21 484.2 2.2 22 459.4 2.04 23 297.4 1.26 24 524.5 2.44 25 496.5 2.35 26 448.5 2.18 27 359.2 2.09 28 502.2 2.15 29 367.2 2.31 30 462.4 2.53 31 372.2 1.83 32 477.2 2.2 33 476.5 2.29 35 357.2 1.99 36 428.2 2.08 37 307.2 1.01 38 464.2 2.1 39 433.2 2.14 40 546.4 2.53 41 496.4 2.28 42 389.2 2.22 43 411.4 2.31 44 496.5 2.31 45 496.4 2.29 46 414.5 2.26 47 472.3 2.08 48 451.2 2.1 49 476.2 2.08 50 510.5 2.12 51 365.2 2.11 52 345.2 1.91 53 480.2 2.35 54 447.2 2.22 55 381.2 2.21 56 398.2 2.07 57 498.5 2.28 59 514.4 2.2 60 418.3 2.22 61 400.5 1.89 62 428.2 2.12 63 476.4 2.63 65 448.2 1.77 66 550.4 2.6 67 472.3 2.06 68 395 2.6 69 512.5 2.41 70 387.2 2.02 71 414.2 1.98 72 325.5 1.94 73 510.3 2.4 74 428.2 2.19 75 347 1.57 76 460.5 2.11 77 484.2 2.3 78 476 2.34 79 418.3 2.24 80 532.5 2.33 81 410.3 2.27 82 460.5 2.12 83 526.6 2.09 84 480.2 2.28 85 331.3 1.98 87 498.5 2.29 88 483.3 2.15 89 547.4 2.49 90 490.4 2.16 91 447.2 2.23 92 400.3 2.16 93 544.5 2.29 94 444.5 2.29 95 399.2 2.31 96 488.7 2.25 97 460.5 2.95 98 432.5 2.33 99 405.2 2.36 100 467.4 2.41 101 351.2 2.11 102 428.2 2.18 103 466.4 2.09 104 308.2 2.08 105 463.4 1.45 106 516.5 2.61 107 377.4 2.29 108 473.4 2.35 109 384.3 1.72 110 297.5 1.7 111 315.3 1.65 112 544.5 2.3 113 390.2 1.76 114 448.4 2.37 115 516.5 2.51 116 397.3 2.59 117 520.5 2.33 118 353.4 2.62 120 475.2 2.05 122 492.5 2.53 123 415.2 2.29 124 443 2.33 125 528.3 2.6 126 462.4 2.23 127 457.4 2.19 128 452.2 2.06 129 404.5 2.09 130 501.3 2.21 131 373.2 2.31 132 404.4 1.76 133 429 2.39 134 399.2 2.02 135 333.2 1.47 136 430.2 2.07 137 414.4 1.99 138 339.3 1.97 139 398.2 2.21 140 430.5 2.29 141 420.2 1.95 142 432.4 2.08 143 341.2 1.78 144 467.4 1.78 145 448.2 2.36 146 480.2 2.24 148 494.5 2.56 150 492.4 2.25 151 426.3 2.32 152 290 2.16 153 370.3 1.6 154 419.2 2.03 155 305.2 1.88 156 375 1.92 157 319.2 2 158 339.3 1.92 159 341.3 2.96 160 417.5 2.35 161 353.3 2.25 162 532.5 2.33 163 343 2.03 164 344 2.56 165 468.2 1.16 166 500.5 2.78 167 446.4 2.12 168 436.2 1.84 169 495.4 2.27 170 480.3 2.93 171 339.3 1.92 172 422.2 2 173 420.2 2.07 174 456.5 2.4 175 302.3 2.16 176 393.2 2.42 177 540.4 2 178 322.4 2.17 179 470.5 2.51 180 351.3 2.22 181 318 2.38 182 400.2 1.86 183 313 1.46 184 341.2 1.87 185 351.4 1.86 186 425 2.15 187 331 1.89 188 501.3 2.19 189 552.6 2.52 191 358 1.68 192 488.3 2.25 193 492.4 2.25 194 460.4 2.49 195 516.5 2.56 196 327.2 1.62 197 525.6 2.44 198 544.5 2.3 199 384.2 2.06 200 483.4 2.35 202 432.5 2.31 203 388.2 2.12 204 302.3 2.14 205 412 1.86 206 329.5 0.92 207 316.2 2.45 208 406.4 2.29 209 475.2 2.04 210 345.2 1.94 211 419.4 2.12 212 431.4 1.96 213 351.2 2.11 214 456.5 2.38 215 491.2 2.25 216 532.5 2.33 217 410.2 2.26 218 351.2 2.11 219 388.2 2.04 220 462.4 2.54 221 504.4 2.14 222 510.4 2.35 223 461.4 2.24 224 317 1.8 225 470.5 2.43 226 373 2.23 227 389.2 2.28 228 403.2 1.93 229 446.2 2.21 230 483.4 2.3 232 375 2.08 233 552.5 2.25 234 463.2 1.49 235 432.5 2.24 236 399.2 2.03 238 308.2 2.09 239 303.3 1.73 240 345.2 2.28 241 NA NA 242 313.2 1.88 243 544.5 2.31 244 297.5 1.59 245 426.2 2.05 246 395.2 2.28 247 431.5 2.46 248 359.2 2.08 249 418.4 1.98 250 414.4 1.91 251 357.2 1.99 252 414.5 2.35 253 487.4 2.18 254 444.4 2.23 255 459.4 2.02 256 434.4 2.05 257 308.2 2.09 258 409.2 2.68 259 297.2 1.78 260 467.4 1.74 261 355.4 1.94 262 496.4 2.25 263 294.4 2.33 264 297.4 1.24 265 463.2 2.04 266 432.4 2.04 267 484.2 2.27 268 333.5 1.84 269 418.3 2.23 270 446.4 2.29 271 424.2 2.38 272 283.3 1.34 273 403.4 2.17 275 383 2.47 276 320.2 2.37 278 411.2 2.12 279 442.5 2.08 280 341.2 1.85 281 472.4 2.44 282 446.4 2.24 283 403.5 2.21 284 434.5 2.05 285 383.2 2.53 286 417.5 2.36 287 474.3 2.58 288 336.4 2.17 289 402.4 2.16 290 475.2 1.89 291 339.5 0.51 292 392.2 2.13 293 430.5 2.14 294 480.5 2.48 295 530.2 2.55 296 473.4 2.11 297 516.5 2.65 298 526.6 2.57 299 291 0.45 300 316.2 1.44 301 426.2 1.98 302 484.5 2.61 303 432.5 2.13 304 532.3 2.31 305 351.3 2.22 306 428.5 2.38 307 418.4 1.84 309 418.4 1.9 310 388.5 1.66 311 486.5 2.3 313 294 2.33 315 428 1.85 316 428.2 1.95 317 418.6 1.97 318 426.3 2.1 319 372.2 1.79 320 403.2 2.23 321 457.2 2.07 322 430.2 1.94 323 339.1 1.92 324 432.4 2.14 325 289.2 0.77 326 383.2 2.3 327 386 1.92 328 331.2 2.11 329 500.3 2.86 330 480.2 2.38 331 467.4 2.01 332 397.27 1.79 333 319.2 1.86 334 313 2.01 335 484.2 2.34 336 426 1.96 337 353.2 1.84 338 431.4 1.97 339 367.3 2.3 340 416.2 1.76 341 347 2.41 342 285.3 1.65 343 316.8 1.64 344 502.4 2.17 345 470.5 2.48 346 458.4 2.35 347 397.2 2.47 348 331.3 1.96 349 494.3 2.3 350 297.3 1.04 351 404.5 1.9 352 344 0.7 353 457.4 2.22 354 437.2 2.48 355 411.4 2.31 356 417.4 1.94 357 403 2.19 358 341.2 1.77 359 426 1.79 360 473.4 2.35 361 516.5 2.5 362 459.2 1.96 363 445.3 2.08 364 424 1.8 365 369.2 2.41 366 369.2 2.14 367 355.2 2.02 368 401.25 1.75 369 332.2 2.4 370 452.2 2.19 371 430.2 1.94 372 313.1 1.55 373 487.4 2.19 374 390.3 1.98 375 271.2 0.59 376 314 2.39 377 315.3 1.66 378 419.2 1.97 379 482.5 2.55 380 414.5 2.28 381 404.4 1.75 382 411.4 2.75 383 452.3 2.17 384 466.4 2.23 385 369 2.19 386 460.5 2.51 387 331 1.78 388 508.5 2.21 389 470.5 2.5 390 458.5 2.12 391 420.3 2.08 392 351.2 2.11 393 345.2 2.03 394 408.2 1.72 395 432.4 2.01 396 502.2 2.34 397 311.3 1.72 398 442.5 2.08 399 428.2 2.06 400 368 1.97 401 510.4 2.27 402 516.5 2.51 403 456.5 2.17 404 428.3 2.36 405 504.5 2.53 406 505.4 1.81 407 426 2.1 408 351.2 2.11 409 486.5 2.7 410 484.2 2.3 411 552.5 2.25 412 444.4 1.81 413 404.5 2.11 414 357.2 2.39 415 322.4 2.15 416 301.2 1.23 417 446.2 2.04 418 446.3 2.02 419 444.5 2.18 420 297.5 1.61 421 351.2 2.11 422 504.5 2.51 423 400.5 2.16 424 446.3 2.01 425 399.2 2.31 426 452.4 2.28 427 434.4 2.21 428 476.2 2.09 429 316.2 1.4 430 400.3 1.88

Example 62 Assays

Functional Mobilization of Intracellular Calcium to Determine Muscarinic Receptor Activity:

CHO cells expressing muscarinic receptors (M₁ to M₅) are grown as monolayers in tissue culture flasks at 37° C. in a humidified atmosphere containing 5% CO₂ and passaged every 3-5 days. The growth media is Dulbecco's modified eagles medium (DMEM, Gibco Cat#12430-054), containing 25 mM Hepes and supplemented with Fetal Bovine Serum (Hyclone, cat# SH30071.03), 0.1 mM of MEM non-essential amino acids (GIBCO, Cat#11140-050), 1 mM MEM Sodium Pyruvate (GIBCO Cat#11360-070) and 100 units/ml of Penicillin G and 100 μg/ml of Streptomycin (GIBCO Cat#15140-122). The recombinant muscarinic receptor cell lines are grown under antibiotic pressure with media containing 25 μg/ml zeocin and 500 μg/ml G418 (M1-CHO), 4 μg/ml puromycin, 50 μg/ml zeocin and 2.5 μg/ml blasticidin (M2 and M4-CHO) or 50 μg/ml zeocin and 4 μg/ml puromycin (M3 and M5-CHO).

Cells are harvested at 80-90% confluence using Versene (GIBCO Cat#15040-066), collected by centrifugation and seeded 18-24 hrs prior to running the calcium assay at a density of 5,000-10,000 cells/well in back-walled, clear-bottomed 384-well plates (BD Biocoat, poly-D-lysine, Cat#356663). The day of the experiment, the cells are washed with a plate washer (Bioteck Instruments, ELX 405) using bath1 buffer (140-mM NaCl, 4.5-mM KCl, 2-mM CaCl₂, 1-mM MgCl₂, 10-mM Hepes-Na, 10-mM Glucose, pH 7.4, with NaOH) containing 1 mM Probenecid. Next, the calcium dye Fluo-3 (25 μl/well of Fluo-3 AM at 4 μM, Molecular Probes F-1241, in Bath 1 buffer containing 1 mM Probenecid) is added to the 25 μl of Bath 1 remaining in each well after the plate wash and the dye is loaded at 37° C. in the tissue culture incubator for 60-90 min. The fluorescent dye is removed using the plate washer with Bath 1 containing 1 mM Probenecid, leaving 25 μl/well of this solution after the wash. Alternatively, cells can be loaded with the calcium indicator from Molecular Devices (Calcium 3 Assay Reagents, Cat # R7181) adding 5 μl of a 5× solution dye in Bath 1 containing 1 mM Probenecid (10 ml per dye flask cat# R7182 to generate a solution 20×) to 20 μl of the same buffer. After loading for 60 min, the experiment can be run without having to remove the dye.

Compounds are prepared at a 2× fold concentration in a 96-well plate (round bottom, Costar Corning cat#3656), by reconstituting the pre-spotted compounds in bath 1 containing 1 mM probenecid. The final concentration DMSO is 0.5%, and the amount of DMSO is normalized across the assay plate. To determine an agonist action of the compounds on muscarinic receptors, the reconstituted compounds are added (25 μl compound/well) to the cell assay plate (containing 25 μl/well) using the multi-channel robotic system of the FLIPR 3 Instrument (Molecular Devices, Sunnyvale, Calif.). To determine a functional inhibitory action of the compounds on muscarinic receptors, the reconstituted compounds are added (25 μl compound/well) to the assay plate and pre-incubated for 15 min prior to adding 25 μl of Carbachol at 3× the EC80 for each muscarinic subtype. Alternatively, the compounds can be co-applied simultaneously with the agonist. In both assay modes, the fluorescence is recorded for 60 sec (excitation wavelength is 488 nM and emission wavelength 540 nm) using the FLIPR 3 instrument.

The potency, efficacy and selectivity of the muscarinic compounds were evaluated by screening the compound activity across the whole family (M₁ to M₅ cells). Compounds were also screened for activity on other proteins such as other GPCRs and ion channels to determine selectivity on M4 receptors.

The compounds of the present invention were found to modulate the M₁ and/or M₄ muscarinic receptors selectively over the other receptor types.

Examples of activities and efficacies of the muscarinic compounds of formulae (I and II) on modulating M₁ and M₄ receptors are shown below in Table 2. The compound activity for the M₁ and M₄ receptor is illustrated with “xxx” if activity was measured to be less than 0.1 μM, “xx” if activity was measured to be between 0.1 μM and 1.0 μM, and “x” if activity was measured to be greater than 1.0 μM. The efficacy for M₁ and M₄ modulation is illustrated with “xxx” if efficacy was calculated to be greater than 85%, “xx” if efficacy was calculated to be between 85% and 65%, and “x” if efficacy was calculated to be less than 65%.

TABLE 2 Compound activities and efficacies for modulating M₁ and M₄ receptors Cmd M₁ M₄ M₁ M₄ No. Activity Activity Efficacy Efficacy 1 xx xx xx xxx 2 x x x x 3 xxx xx xx xx 4 xxx x x x 5 xxx xxx xx xxx 6 xxx xx xx xx 7 xxx xx xx xxx 8 xx xx x xx 9 xxx x xx xx 10 xx xx xx xx 11 x x x x 12 xxx xx x x 13 xx x xx x 14 xxx xxx xx xxx 15 xxx xx xx xxx 16 xxx xxx xx xx 17 xx xx x xx 18 xxx xx x xxx 19 xxx xx xx xx 20 x xx x x 21 xx x x x 22 xxx x xx x 23 xx x x x 24 xx x x x 25 xxx xxx xx xxx 26 xxx xx xx x 27 xxx xxx xx xx 28 xxx xx xxx xx 29 xxx xxx xxx xxx 30 xxx xxx xxx xxx 31 xxx xxx xxx xx 32 xxx xxx xxx xx 33 xxx xxx xxx xxx 34 xxx xx xx xxx 35 xxx xx xxx xxx 36 xxx xx xx xxx 37 xxx xx xx xxx 38 xxx xxx xxx xxx 39 xxx xx xx xxx 40 xxx xx xx xxx 41 xxx xxx xxx xxx 42 xxx xx xxx xxx 43 xxx x xxx xxx 44 xxx xx xx xxx 45 xxx xxx xxx xx 46 xxx xxx xxx xx 47 xxx xx xx xx 48 xxx xx xxx xx 49 xxx xxx xxx xx 50 xxx xx xxx xxx 51 xxx xx xx xx 52 xxx xxx xxx xx 53 xx xx x xx 54 xxx xx xxx xx 55 xxx xxx xxx xx 56 xxx xxx xx xx 57 xxx xxx xx xx 58 xxx xx xx xx 59 xxx xx x xx 60 xx x xx xx 61 xxx xx xx xx 62 xxx xx x xx 63 xxx x x x 64 xxx xx x x 65 xx x xx x 66 xxx xxx xxx xxx 67 xxx xx x x 68 xx x x x 69 xx xx x x 70 xx x xx xx 71 xxx xx x x 72 xxx xx xx xx 73 xxx xx xx xx 74 xxx xx xx xx 75 xxx xx x xx 76 xxx xx xx xx 77 xxx xx xx x 78 xxx xx xx x 79 xx x x x 80 xx xx x x 81 xx x x x 82 xxx xx xx xx 83 xxx x x x 84 xxx xx xx xx 85 xxx xx xx xx 86 xxx x xx x 87 xxx x xx x 88 xxx xx xx x 89 xxx xx xx x 90 xx x xx x 91 xxx xx xx x 92 xxx xx xx x 93 xx xx x x 94 xxx xx x x 95 xxx xx xx x 96 xx x xx x 97 xxx x xx x 98 xxx xx xx x 99 xxx x x x 100 xxx xx xx xx 101 xxx xx xx xx 102 xxx xx xx xx 103 xxx xx xx x 104 xxx x xx x 105 xx x x x 106 xxx xx xx x 107 xxx x xx x 108 xxx xx xx x 109 xxx xx xx x 110 xxx xx x x 111 xxx xx xx x 112 xxx xx xx x 113 xxx x xx x 114 xx x xx x 115 xxx xx xx x 116 xxx xx xx x 117 xxx xx xx x 118 xxx x xx x 119 xxx x x x 120 xx x x x 122 xxx xx xx x 123 xx x x x 124 xxx xx x x 125 xxx xx xx x 126 xxx x x x 127 xxx xx xx x 128 xxx xx x x 129 xxx x xx x 130 xxx xx x x 131 xxx xx xx xxx 132 xxx xxx xxx xxx 133 xxx xx xxx xx 134 xxx xx xxx x 135 xxx xx xxx xxx 136 xxx xxx xxx xxx 137 xxx x xxx xxx 138 xxx x xx xx 139 xxx xxx xxx xxx 140 xxx xxx xxx xxx 141 xxx xx xxx xxx 142 xxx x xx xxx 143 xxx xxx xx xxx 144 xxx xxx xxx xxx 145 xxx x xxx xxx 146 xxx xxx xxx xxx 147 xxx xx xx xxx 148 xxx xx xx xxx 149 xxx x xxx xxx 150 xxx x xx xxx 151 xxx xxx xxx xxx 152 xx x xx xxx 153 xxx xxx xxx xxx 154 xxx xxx xx xxx 155 xxx x xxx xxx 156 xxx xxx xx xxx 157 xxx x xx xxx 158 xxx x xxx xxx 159 xx x xxx xxx 160 xxx xx xxx xxx 161 xx x xxx xxx 162 xxx x xx xxx 163 xxx xx xx xxx 164 xx x xxx xxx 165 x x xx xxx 166 xxx x xxx xxx 167 xxx xx xx xxx 168 xx xx xxx 169 xxx x xx xxx 170 xx x xx xxx 171 xx x xxx xx 172 x x xxx xx 173 xxx xx xx xxx 174 xxx x xxx xx 175 xxx xx xx xx 176 xx xx xxx xx 177 xxx xx xx xx 178 xx x xxx xx 179 xx x xxx xx 180 xxx xxx xx xx 181 xx x xx xx 182 x x xx xx 183 xx x xx xx 184 xx x xxx xx 185 x x xx xx 186 xxx x xxx xx 187 xx x xx xx 188 x x x xx 189 xxx x xx xx 190 x x xxx xx 191 xxx x xx xx 192 xxx x xx xx 193 x x x x 194 xxx x xxx xx 195 xx x x x 196 xxx x xx x 197 xx x x x 198 xx x xx x 199 xx x xx x 200 xx x xx x 202 xx x xx x 203 xxx xx xx x 204 xxx x xx x 205 x x x x 206 xxx x xx x 207 xx x xx x 208 xx x x x 209 xx x xxx x 210 xx x xx x 211 x x xx x 212 x x x x 213 xx x xx x 214 x x x x 215 xx x x x 216 xxx x xxx x 217 xx x x x 218 xx x x x 219 x x xx x 220 x x xx x 221 xx x xx x 222 x x x x 223 x x x x 224 x x xx x 225 x x x x 226 x x x x 227 xxx xxx xxx xxx 228 x x x x 229 xx xxx x xxx 230 x xx x xxx 231 x x xx xxx 232 xx xxx x xxx 233 xxx xxx xx xxx 234 xxx xxx xx xx 235 xx x xx xx 236 xxx xx xx xx 237 xxx xx x x 238 x x x x 239 x x xx xx 240 xx x xx xxx 241 xx x x xxx 242 xxx xx xx xxx 243 xxx x xx xx 244 xx x xx xx 245 xx xx x xxx 246 xx xx x xxx 247 xx x xx xxx 248 xx x xx x 249 x x xx xx 250 xx x xx xx 251 xx x xx xx 252 x x x xx 253 xx x xx xx 254 x x xx xx 255 x x x x 256 xx xx x x 257 x x xxx x 258 x x xx x 259 x x xx x 260 xxx x xx x 261 xx x x x 262 x x x x 263 xxx xxx x x 264 x x x x 265 xx xx x x 266 x x x x 267 x x x x 268 x x x x 269 xxx xxx xx xxx 270 xxx xxx xx xxx 271 xxx xxx xx x 272 xxx xxx xx xxx 273 xxx xx xxx xxx 274 xxx x xx xxx 275 xxx xx xx xxx 276 xxx x xx xx 277 xxx x xx x 278 xx xx xx xx 279 xx xx x x 280 x x xx xx 281 xx xx x xx 282 xxx xx x xx 283 xx x xx xx 284 xx xx x x 285 xx x x x 286 xx x x x 287 xx x x x 288 x x x x 289 xxx x x x 290 xxx x x x 291 xx x xx xx 292 xx x xx xx 293 xx xxx xxx xxx 294 xx xx xxx xx 295 xxx xxx xx xx 296 x x xx xx 297 x x xx xx 298 x x x xx 299 x x xx xx 300 xx x xx x 301 x x x x 302 x x x x 303 xx x xxx x 304 xxx x xx x 305 x x x x 306 x x x x 307 xx x xx x 308 xxx x xxx x 309 xx x xxx x 310 xx x x x 311 xxx x xx xx 312 x x x x 313 x x x x 314 xx x x x 315 x x x x 316 x x x x 317 x x x x 318 xxx xxx xx xxx 319 xx x x x 320 xx x xx x 321 xx x xx xx 322 xx xxx x xxx 323 xx x xx xx 324 xx x xx xx 325 x x xx x 326 x x x x 327 x x x x 328 xx x x xx 329 xxx x xx x 330 x x x x 331 xx x x x 332 x x x x 333 x x x x 334 x x x x 335 x x x x 336 x x x x 337 x x x x 338 x x x x 339 x x x x 340 xx x x x 341 x x x x 342 xxx xx xx xx 343 xxx xxx xx x 344 xxx xx xx x 345 xxx xx x x 346 xxx x x x 347 xxx xx xx xxx 348 xxx xx xxx xxx 349 xx xx xxx xxx 350 xxx xxx xxx xxx 351 xxx xx xx xxx 352 xxx x xxx xxx 353 xxx x xxx xx 354 x x xx xx 355 xx xx xx xx 356 xxx x xxx xx 357 xx x x x 358 xxx xx xx xx 359 xx xx x x 360 xx x xx x 361 xx x x x 362 xx x xx x 363 xx x x x 364 xxx x xxx x 365 xxx x xx x 366 xx x x x 367 x x x x 368 xxx xx x x 369 xxx xx xxx xxx 370 xxx xx xx xxx 371 xxx x xx xxx 372 xxx xx xx xxx 373 xxx xx xx xxx 374 xx x xx xx 375 xxx xxx xxx xx 376 xxx x xx xx 377 xxx xx xx xx 378 xx x xx xx 379 xxx xx xx xx 380 xxx xx xx xx 381 xxx x xx x 382 xxx x xx xx 383 xxx xx xx x 384 xx x x x 385 xx x xx x 386 xx xx x x 387 xxx xx xx x 388 xxx x xx x 389 xx x xx x 390 xxx x xx x 391 xx x x x 392 xxx x xx x 393 xxx x xx x 394 xxx xx x x 395 xxx x x x 396 xx x x x 397 xx x xx x 398 xx x x x 399 xx xx xx x 400 x x x x 401 xxx x xx x 402 xx x xx x 403 xxx x xx x 404 xx x x x 405 xx x x x 406 xx x x x 407 xx x x x 408 xxx xxx xx xx 409 xxx xxx xxx xxx 410 xx xx x x 411 xxx xx x x 412 xx x x x 413 xxx xx x x 414 x x x x 415 x x x x 416 x x x x 417 xx x x x 418 x x x x 419 x x x x 420 xx x x x 421 x x x x 422 xxx x x x 423 xx x x x 424 x x x x 425 x x x x 426 x x x x 427 xx x x x 428 xx x x x 429 xx x x x 430 xx x x x 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460

Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 

1. A method of modulating activity of an M₁ or M₄ muscarinic receptor, comprising the step of contacting said receptor with a compound of formula (I)

or pharmaceutically acceptable salts thereof, wherein Each of R₁, R₂, R₃ is independently Q₁ or Q₂; Z₁ is —N(Q₁)- or —N(Q₂)-; Z₂ is N; L is a bond, an aliphatic group, C₃-C₆ cycloaliphatic, —O—, —S(O)_(z)—, —S(O)_(z)—(C₁-C₄)alkyl-, or —S(O)_(z) N(Q₂)-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q₁, or Q₂; G is a monocycloheteroaliphatic group, selected from pyrrolidine, piperidine and azepane, or G is an adamantyl, or a bicyclic or a tricyclic group of the formula (III)

in which the monocycloheteroaliphatic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X₁ and ring B, and the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ₄, fluorine, Q₂, —C(O)—X₂-aliphatic in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃; Bond r is a single or double bond and when ring B is present, bond r is fused with B; Ring B, when present, is a 5-6 membered cycloaliphatic or heterocycloaliphatic ring, and is optionally substituted with 1-3 of oxo, Q₁, or Q₂; X₁ is —(CH₂)_(i)—, —O—, —S—, —N(Q₂)-, or —N(—C(O)—X₂-aliphatic) in which X₂ is absent, —O—, —NH—, —NQ₂-, or —S(O)_(z)— and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃; Each Q₁ is independently halo, —CN, —NO₂, —OQ₂, —S(O)_(z)Q₂, —S(O)_(z)N(Q₂)₂, —N(Q₂)₂, —C(O)OQ₂, —C(O)-Q₂, —C(O)N(Q₂)₂, —C(O)N(Q₂)(OQ₂), —N(Q₂)C(O)-Q₂, —N(Q₂)C(O)N(Q₂)₂, —N(Q₂)C(O)O-Q₂, —N(Q₂)S(O)_(z)-Q₂ or aliphatic optionally including 1-3 substituents independently selected from Q₂ or Q₃; Each Q₂ is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q₃; Each Q₃ is halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —S(O)_(z)Q₄, —N(Q₄)₂, —COOQ₄, —C(O)Q₄, —OQ₄, or C₁-C₄ alkyl optionally substituted with halo, oxo, —CN, —NO₂, —CF₃, —OCF₃, —OH, —SH, —S(O)_(z)H, —NH₂, or —COOH; Each Q₄ is aliphatic, cycloaliphatic, aryl, aralkyl, heterocycloaliphatic, heteroaralky, or heteroaryl, each optionally including 1-3 substituents selected from halo, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, or COOH; Each Q₅ is a heterocyclic ring optionally including 1-3 substituents selected from halo, C₁-C₄alkyl, oxo, CN, NO₂, CF₃, OCF₃, OH, SH, —S(O)_(z)H, —NH₂, COOH; Each i is independently 1, 2, or 3; Each m and n is 2; Each p is 0; Each y is independently 0 or 1; Each t is 1 to 4; and Each z is independently 0, 1, or
 2. 2. The method of claim 1, wherein G is substituted with alkyl, aryl, haloalkyl, alkoxycarbonyl, or alkoxyamino.
 3. The method of claim 1, wherein G is an optionally substituted 5 to 7 membered monoheterocycloaliphatic group selected from pyrrolidine, piperidine and azepane.
 4. The method of claim 3, wherein G is substituted with 1 to 2 substituents independently selected from Q₂, and —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.
 5. The method of claim 3, wherein G is substituted with 1 to 2 substituents independently selected from alkoxycarbonyl, alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl, heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl.
 6. The method of claim 1, wherein G is one selected from


7. The method of claim 1, wherein G is an optionally substituted bicyclic group of formula (III) in which ring B is absent.
 8. The method of claim 7, wherein X₁ is —(CH₂)_(i).
 9. The method of claim 8, wherein G is optionally substituted bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptanyl.
 10. The method of claim 9, wherein G is substituted with 1 to 2 substituents independently selected from Q₂, and —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.
 11. The method of claim 7, wherein X₁ is —N(Q₂)- or —N(C(O)—X₂-aliphatic)-, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.
 12. The method of claim 11, wherein G is an optionally substituted tropane.
 13. The method of claim 12, wherein the tropane is substituted with Q₂ or —C(O)—X₂-aliphatic, where X₂ is absent, —O—, —NH—, or —NQ₂-, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q₃.
 14. The method of claim 13, wherein the tropane is substituted at the tropane ring nitrogen atom with alkoxycarbonyl, alkoxyalkoxycarbonyl, heterocycloalkoxycarbonyl, cycloalkoxycarbonyl, alkoxyaryloxycarbonyl, alkylaminocarbonyl, haloalkoxycarbonyl, alkynyloxycarbonyl, or heterocycloalkylalkoxycarbonyl.
 15. The method of claim 14, wherein G is selected from


16. The method of claim 1, wherein Z₁ is —NH—, or —N(Q₁)-.
 17. The method of claim 16, wherein Z₁ is —N(Q₁)- and Q₁ is alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, aminocarbonyl, alkylcarbonylalkyl, alkoxyalkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, alkoxycarbonyl, haloarylcarbonyl, haloarylsulfonyl, alkylheteroarylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, haloarylaminocarbonyl, alkylheteroarylsulfonyl, cyanoalkylarylcarbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkoxyarylcarbonyl, haloalkoxycarbonyl, alkylarylcarbonyl, haloalkoxyarylcarbonyl, or arylaminocarbonyl.
 18. The method of claim 16, wherein Z₁ is one selected from —NH—,


19. The method of claim 1, wherein R₁ is selected from hydrogen, halo, or optionally substituted alkyl, heteroaryl, alkoxy, alkenyl, cycloalkyl, cyanoalkylaryl, alkylaryl, alkylsulfonylaryl, alkylcarbonylaryl, aryl, aminocarbonylaryl, alkylcarbonylaminoaryl, cycloalkenyl, and alkoxyaryl.
 20. The method of claim 19, wherein R₁ is selected from hydrogen, halo, methyl,


21. The method of claim 1, wherein R₂ and R₃ are independently hydrogen or alkyl.
 22. The method of claim 21, wherein R₂ and R₃ are both hydrogen.
 23. The method of claim 1, wherein L is a bond or an aliphatic group optionally substituted with 1-3 of oxo, Q₁, or Q₂.
 24. The method of claim 23, wherein L is a bond.
 25. The method of claim 23, wherein L is —CH₂—.
 26. A method of treating or reducing the severity of a disease or condition in a patient, wherein said disease or condition is selected from pain, schizophrenia, Parkinson's disease, glaucoma, or Attention Deficit Hyperactivity Disorder (ADHD), wherein said method comprises the step of contacting said patient with a compound as described in of claim
 1. 27. A method of modulating activity of an M₁ or M₄ muscarinic receptor, comprising the step of contacting said receptor with a compound selected from:  3

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28. The method of claim 26, wherein the disease or condition is selected from Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, Parkinson's disease and Glaucoma.
 29. The method of claim 26, wherein the disease or condition is pain. 